Proteins and nucleic acids encoding same

ABSTRACT

Disclosed are polypeptides and nucleic acids encoding same. Also disclosed are vectors, host cells, antibodies and recombinant methods for producing the polypeptides and polynucleotides, as well as methods for using same.

RELATED APPLICATIONS

[0001] This application claims priority from Provisional ApplicationsU.S. S. No. 60/258,928, filed Dec. 29, 2000, U.S. S. No. 60/259,415,filed Jan. 2, 2001, U.S. S. No. 60/259,785, filed Jan. 4, 2001, U.S. S.No. 60/269,814, filed Feb. 20, 2001, U.S. S. No. 60/279,832, filed Mar.29, 2001, U.S. S. No. 60/279,833, filed Mar. 29, 2001, U.S. S. No.60/279,863, filed Mar. 29, 2001, U.S. S. No. 60/283,889, filed Apr. 13,2001, U.S. S. No. 60/284,447, filed Apr. 18, 2001, U.S. S. No.60/286,683, filed Apr. 25, 2001, U.S. S. No. 60/294,080, filed May 29,2001, U.S. S. No. 60/312,915, filed Aug. 16, 2001, U.S. S. No.60/313,325, filed Aug. 17, 2001, U.S. S. No. 60/322,699, filed Sep. 17,2001, U.S. S. No. ______ (bearing attorney docket number 21402-234E4),filed Nov. 26, 2001, each of which is incorporated by reference in itsentirety.

FIELD OF THE INVENTION

[0002] The invention relates to polynucleotides and the polypeptidesencoded by such polynucleotides, as well as vectors, host cells,antibodies and recombinant methods for producing the polypeptides andpolynucleotides, as well as methods for using the same.

BACKGROUND OF THE INVENTION

[0003] The invention generally relates to nucleic acids and polypeptidesencoded therefrom. More specifically, the invention relates to nucleicacids encoding cytoplasmic, nuclear, membrane bound, and secretedpolypeptides, as well as vectors, host cells, antibodies, andrecombinant methods for producing these nucleic acids and polypeptides.

SUMMARY OF THE INVENTION

[0004] The invention is based in part upon the discovery of nucleic acidsequences encoding novel polypeptides. The novel nucleic acids andpolypeptides are referred to herein as NOVX, or NOV1, NOV2, NOV3, NOV4,NOV5, NOV6, NOV7, NOV8, NOV9, NOV10, NOV11, NOV12, NOV13, NOV14, NOV15,NOV16, NOV17, NOV18, NOV19, and NOV20 nucleic acids and polypeptides.These nucleic acids and polypeptides, as well as variants, derivatives,homologs, analogs and fragments thereof, will hereinafter becollectively designated as “NOVX” nucleic acid or polypeptide sequences.

[0005] In one aspect, the invention provides an isolated NOVX nucleicacid molecule encoding a NOVX polypeptide that includes a nucleic acidsequence that has identity to the nucleic acids disclosed in SEQ IDNOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59. In some embodiments,the NOVX nucleic acid molecule will hybridize under stringent conditionsto a nucleic acid sequence complementary to a nucleic acid molecule thatincludes a protein-coding sequence of a NOVX nucleic acid sequence. Theinvention also includes an isolated nucleic acid that encodes a NOVXpolypeptide, or a fragment, homolog, analog or derivative thereof. Forexample, the nucleic acid can encode a polypeptide at least 80%identical to a polypeptide comprising the amino acid sequences of SEQ IDNOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36,38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60. The nucleic acid canbe, for example, a genomic DNA fragment or a cDNA molecule that includesthe nucleic acid sequence of any of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49,51, 53, 55, 57, and 59.

[0006] Also included in the invention is an oligonucleotide, e.g., anoligonucleotide which includes at least 6 contiguous nucleotides of aNOVX nucleic acid (e.g., SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19,21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55,57, and 59) or a complement of said oligonucleotide.

[0007] Also included in the invention are substantially purified NOVXpolypeptides (SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and60). In certain embodiments, the NOVX polypeptides include an amino acidsequence that is substantially identical to the amino acid sequence of ahuman NOVX polypeptide.

[0008] The invention also features antibodies that immunoselectivelybind to NOVX polypeptides, or fragments, homologs, analogs orderivatives thereof.

[0009] In another aspect, the invention includes pharmaceuticalcompositions that include therapeutically- or prophylactically-effectiveamounts of a therapeutic and a pharmaceutically-acceptable carrier. Thetherapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or anantibody specific for a NOVX polypeptide. In a further aspect, theinvention includes, in one or more containers, a therapeutically- orprophylactically-effective amount of this pharmaceutical composition.

[0010] In a further aspect, the invention includes a method of producinga polypeptide by culturing a cell that includes a NOVX nucleic acid,under conditions allowing for expression of the NOVX polypeptide encodedby the DNA. If desired, the NOVX polypeptide can then be recovered.

[0011] In another aspect, the invention includes a method of detectingthe presence of a NOVX polypeptide in a sample. In the method, a sampleis contacted with a compound that selectively binds to the polypeptideunder conditions allowing for formation of a complex between thepolypeptide and the compound. The complex is detected, if present,thereby identifying the NOVX polypeptide within the sample.

[0012] The invention also includes methods to identify specific cell ortissue types based on their expression of a NOVX.

[0013] Also included in the invention is a method of detecting thepresence of a NOVX nucleic acid molecule in a sample by contacting thesample with a NOVX nucleic acid probe or primer, and detecting whetherthe nucleic acid probe or primer bound to a NOVX nucleic acid moleculein the sample.

[0014] In a further aspect, the invention provides a method formodulating the activity of a NOVX polypeptide by contacting a cellsample that includes the NOVX polypeptide with a compound that binds tothe NOVX polypeptide in an amount sufficient to modulate the activity ofsaid polypeptide. The compound can be, e.g., a small molecule, such as anucleic acid, peptide, polypeptide, peptidomimetic, carbohydrate, lipidor other organic (carbon containing) or inorganic molecule, as furtherdescribed herein.

[0015] Also within the scope of the invention is the use of atherapeutic in the manufacture of a medicament for treating orpreventing disorders or syndromes including, e.g., those described forthe individual NOVX nucleotides and polypeptides herein, and/or otherpathologies and disorders of the like.

[0016] The therapeutic can be, e.g., a NOVX nucleic acid, a NOVXpolypeptide, or a NOVX-specific antibody, or biologically-activederivatives or fragments thereof. For example, the compositions of thepresent invention will have efficacy for treatment of patients sufferingfrom the diseases and disorders disclosed below and/or other pathologiesand disorders of the like. The polypeptides can be used as immunogens toproduce antibodies specific for the invention, and as vaccines. They canalso be used to screen for potential agonist and antagonist compounds.For example, a cDNA encoding NOVX may be useful in gene therapy, andNOVX may be useful when administered to a subject in need thereof. Byway of non-limiting example, the compositions of the present inventionwill have efficacy for treatment of patients suffering from the diseasesand disorders disclosed above and/or other pathologies and disorders ofthe like.

[0017] The invention further includes a method for screening for amodulator of disorders or syndromes including, e.g., the diseases anddisorders disclosed above and/or other pathologies and disorders of thelike. The method includes contacting a test compound with a NOVXpolypeptide and determining if the test compound binds to said NOVXpolypeptide. Binding of the test compound to the NOVX polypeptideindicates the test compound is a modulator of activity, or of latency orpredisposition to the aforementioned disorders or syndromes.

[0018] Also within the scope of the invention is a method for screeningfor a modulator of activity, or of latency or predisposition to andisorders or syndromes including, e.g., the diseases and disordersdisclosed above and/or other pathologies and disorders of the like byadministering a test compound to a test animal at increased risk for theaforementioned disorders or syndromes. The test animal expresses arecombinant polypeptide encoded by a NOVX nucleic acid. Expression oractivity of NOVX polypeptide is then measured in the test animal, as isexpression or activity of the protein in a control animal whichrecombinantly-expresses NOVX polypeptide and is not at increased riskfor the disorder or syndrome. Next, the expression of NOVX polypeptidein both the test animal and the control animal is compared. A change inthe activity of NOVX polypeptide in the test animal relative to thecontrol animal indicates the test compound is a modulator of latency ofthe disorder or syndrome.

[0019] In yet another aspect, the invention includes a method fordetermining the presence of or predisposition to a disease associatedwith altered levels of a NOVX polypeptide, a NOVX nucleic acid, or both,in a subject (e.g., a human subject). The method includes measuring theamount of the NOVX polypeptide in a test sample from the subject andcomparing the amount of the polypeptide in the test sample to the amountof the NOVX polypeptide present in a control sample. An alteration inthe level of the NOVX polypeptide in the test sample as compared to thecontrol sample indicates the presence of or predisposition to a diseasein the subject. Preferably, the predisposition includes, e.g., thediseases and disorders disclosed above and/or other pathologies anddisorders of the like. Also, the expression levels of the newpolypeptides of the invention can be used in a method to screen forvarious cancers as well as to determine the stage of cancers.

[0020] In a further aspect, the invention includes a method of treatingor preventing a pathological condition associated with a disorder in amammal by administering to the subject a NOVX polypeptide, a NOVXnucleic acid, or a NOVX-specific antibody to a subject (e.g., a humansubject), in an amount sufficient to alleviate or prevent thepathological condition. In preferred embodiments, the disorder,includes, e.g., the diseases and disorders disclosed above and/or otherpathologies and disorders of the like.

[0021] In yet another aspect, the invention can be used in a method toidentity the cellular receptors and downstream effectors of theinvention by any one of a number of techniques commonly employed in theart. These include but are not limited to the two-hybrid system,affinity purification, co-precipitation with antibodies or otherspecific-interacting molecules. Unless otherwise defined, all technicaland scientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, suitable methods and materials are described below. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

[0022] Other features and advantages of the invention will be apparentfrom the following detailed description and claims.

DETAILED DESCRIPTION OF TH INVENTION

[0023] The present invention provides novel nucleotides and polypeptidesencoded thereby. Included in the invention are the novel nucleic acidsequences and their polypeptides. The sequences are collectivelyreferred to as “NOVX nucleic acids” or “NOVX polynucleotides” and thecorresponding encoded polypeptides are referred to as “NOVXpolypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” ismeant to refer to any of the novel sequences disclosed herein. Table Aprovides a summary of the NOVX nucleic acids and their encodedpolypeptides. TABLE A Sequences and Corresponding SEQ ID NumbersInternal SEQ ID SEQ ID NOVX Identification NO (nt) NO (aa) Homology 1Sggc_draft_ba186014_2 1 2 Lysosomal Acid Lipase 0000730_dal Precursor 220708613_EXT1 3 4 MEGF/Flamingo/Cadherin 3 CG55806_01 5 6 CoagulationFactor IX Precursor 4 CG55936_01 7 8 Carbonic Anhydrase IV 5 CG55784_019 10 Neural Cell Adhesion Molecule 6 CG55916_01 11 12 Phospholipase CDelta 7 CG55802_01 13 14 3 Alpha Hydroxy Steroid Dehydrogenase 8CG55904_01 15 16 Squalene Desaturase 9 CG55954_01 17 18 LymphocyteAntigen 64 10 CG55910_01 19 20 Acyl-CoA Desaturase 11 CG50281_01 21 22Wnt 10B Protein Precursor 12a CG55920_01 23 24 Kilon Protein Precursor12b CG55920_04 25 26 Kilon Protein Precursor 13a CG55988_01 27 28organic Cation Transporter 13b CG55988_02 29 30 organic CationTransporter 14a CG56001_01 31 32 D-beta Hydroxy HydroxybutyrateDehydrogenase 14b CG56001_02 33 34 D-beta Hydroxy HydroxybutyrateDehydrogenase 15a SC145665404_A/CG55069 35 36 TEN-M3 _01 15b CG55069_0237 38 TEN-M3 15c CG55069_03 39 40 TEN-M3 15d CG55069_08 41 42 TEN-M3 16aCG55778_01 43 44 Aldose Reductase 16b CG55778_02 45 46 Aldose Reductase16c CG55778_03 47 48 Aldose Reductase 16d CG55778_04 49 50 AldoseReductase 16e CG55778_05 51 52 Aldose Reductase 17 CG55982_01 53 54Apolipoprotein A-1 18 CG56747_02 55 56 Apolipoprotein A-1 19 CG55906_0157 58 S3_12 20 CG55906_02 59 60 S3_12

[0024] NOVX nucleic acids and their encoded polypeptides are useful in avariety of applications and contexts. The various NOVX nucleic acids andpolypeptides according to the invention are useful as novel members ofthe protein families according to the presence of domains and sequencerelatedness to previously described proteins. Additionally, NOVX nucleicacids and polypeptides can also be used to identify proteins that aremembers of the family to which the NOVX polypeptides belong.

[0025] The NOVX genes and their corresponding encoded proteins areuseful for preventing, treating or ameliorating medical conditions,e.g., by protein or gene therapy. Pathological conditions can bediagnosed by determining the amount of the new protein in a sample or bydetermining the presence of mutations in the new genes. Specific usesare described for each of the sixteen genes, based on the tissues inwhich they are most highly expressed. Uses include developing productsfor the diagnosis or treatment of a variety of diseases and disorders.

[0026] The NOVX nucleic acids and polypeptides can also be used toscreen for molecules, which inhibit or enhance NOVX activity orfunction. Specifically, the nucleic acids and polypeptides according tothe invention may be used as targets for the identification of smallmolecules that modulate or inhibit, e.g., neurogenesis, celldifferentiation, cell proliferation, hematopoiesis, wound healing andangiogenesis.

[0027] In one embodiment of the present invention, NOVX or a fragment orderivative thereof may be administered to a subject to treat or preventa disorder associated with decreased expression or activity of NOVX.Examples of such disorders include, but are not limited to, cancers suchas adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma,teratocarcinoma, and, in particular, cancers of the adrenal gland,bladder, bone, bone marrow, brain, breast, cervix, gall bladder,ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle,ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin,spleen, testis, thymus, thyroid, and uterus; neurological disorders suchas epilepsy, ischemic cerebrovascular disease, stroke, cerebralneoplasms, Alzheimer's disease, Pick's disease, Huntington's disease,dementia, Parkinson's disease and other extrapyramidal disorders,amyotrophic lateral sclerosis and other motor neuron disorders,progressive neural muscular atrophy, retinitis pigmentosa, hereditaryataxias, multiple sclerosis and other demyelinating diseases, bacterialand viral meningitis, brain abscess, subdural empyema, epidural abscess,suppurative intracranial thrombophlebitis, myelitis and radiculitis,viral central nervous system disease, prion diseases including kuru,Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome,fatal familial insomnia, nutritional and metabolic diseases of thenervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinalhemangioblastomatosis, encephalotrigeminal syndrome, mental retardationand other developmental disorders of the central nervous system,cerebral palsy, neuroskeletal disorders, autonomic nervous systemdisorders, cranial nerve disorders, spinal cord diseases, musculardystrophy and other neuromuscular disorders, peripheral nervous systemdisorders, dermatomyositis and polymyositis, inherited, metabolic,endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis,mental disorders including mood, anxiety, and schizophrenic disorders,akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia,dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette'sdisorder; and disorders of vesicular transport such as cystic fibrosis,glucose-galactose malabsorption syndrome, hypercholesterolemia, diabetesmellitus, diabetes insipidus, hyper- and hypoglycemia, Grave's disease,goiter, Cushing's disease, Addison's disease, gastrointestinal disordersincluding ulcerative colitis, gastric and duodenal ulcers, otherconditions associated with abnormal vesicle trafficking includingacquired immunodeficiency syndrome (AIDS), allergic reactions,autoimmune hemolytic anemia, proliferative glomerulonephritis,inflammatory bowel disease, multiple sclerosis, myasthenia gravis,rheumatoid arthritis, osteoarthritis, scleroderma, Chediak-Higashisyndrome, Sjogren's syndrome, systemic lupus erythiematosus, toxic shocksyndrome, traumatic tissue damage, and viral, bacterial, fungal,helminthic, and protozoal infections, as well as additional indicationslisted for the individual NOVX clones.

[0028] The NOVX nucleic acids and proteins of the invention are usefulin potential diagnostic and therapeutic applications and as a researchtool. These include serving as a specific or selective nucleic acid orprotein diagnostic and/or prognostic marker, wherein the presence oramount of the nucleic acid or the protein are to be assessed. These alsoinclude potential therapeutic applications such as the following: (i) aprotein therapeutic, (ii) a small molecule drug target, (iii) anantibody target (therapeutic, diagnostic, drug targeting/cytotoxicantibody), (iv) a nucleic acid useful in gene therapy (genedelivery/gene ablation), (v) an agent promoting tissue regeneration invitro and in vivo, and (vi) a biological defense weapon. Additionalutilities for the NOVX nucleic acids and polypeptides according to theinvention are disclosed herein.

[0029] NOV1

[0030] A disclosed NOV1 nucleic acid (SEQ ID NO:1) of 1138 nucleotides(also referred to as sggc_draft_ba186014_(—)20000730_da1) encoding anovel LYSOSOMAL ACID LIPASE PRECURSOR-like protein is shown in Table 1A.An open reading frame was identified beginning with an ATG initiationcodon at nucleotides 8-10 and ending with a TAA codon at nucleotides1127-1129. Putative untranslated regions are found upstream from theinitiation codon and downstream from the termination codon, and areunderlined. The start and stop codons are shown in bold letters in Table1A. TABLE 1A NOV1 nucleotide sequence. GTCCAAAATGTGGCTGCTTTTAACAACAACTTGTTTGATCTGTGGAACTTTAAATGCTGGTGGAT (SEQ ID NO:1)TCCTTGATTTGGAAAATGAAGTGAATCCTGAGGTGTGGATGAATACTAGTGAAATCATCATCTACAATGGCTACCCCAGTGAAGAGTATGAAGTCACCACTGAAGATGGGTATATACTCCTTGTCAACAGAATTCCTTATGGGCGAACACATGCTAGGAGCACAGGTCCCCGGCCAGTTGTGTATATGCAGCATGCCCTGTTTGCAGACAATGCCTACTGGCTTGAGAATTATGCTAATGGAAGCCTTGGATTCCTTCTAGCAGATGCAGGTTATGATGTATGGATGGGAAACAGTCGGGGAAACACTTGGTCAAGAAGACACAAAACACTCTCAGAGACAGATGAGAAATTCTGGGCCTTTGGTTTTGATGAAATGGCCAAATATGATCTCCCAGGAGTAATAGACTTCATTGTAAATAAAACTGGTCAGGAGAAATTGTATTTCATTGGACATTCACTTGGCACTACAATAGGGTTTGTAGCCTTTTCCACCATGCCTGAACTGGCACAAAGAATCAAAATGAATTTTGCCTTGGGTCCTACGATCTCATTCAAATATCCCACGGGCATTTTTACCAGGTTTTTTCTACTTCCAAATTCCATAATCAAGGCTGTTTTTGGTACCAAAGGTTTCTTTTTAGAAGATAAGAAAACGAAGATAGCTTCTACCAAAATCTGCAACAATAAGATACTCTGGTTGATATGTAGCGAATTTATGTCCTTATGGGCTGGATCCAACAAGAAAAATATGAATCAGCTTTACCACTCTGATGAATTCAGAGCTTATGACTGGGGAAATGACGCTGATAATATGAAACATTACAATCAGAGTCATCCCCCTATATATGACCTGACTGCCATGAAAGTGCCTACTGCTATTTGGGCTGGTGGACATGATGTCCTCGTAACACCCCAGGATGTGGCCAGGATACTCCCTCAAATCAAGAGTCTTCATTACTTTAAGCTATTGCCAGATTGGAACCACTTTGATTTTGTCTGGGGCCTCGATGCCCCTCAACGGATGTACAGTGAAATCATAGCTTTAATGAAGGCATATTCCTAA ATGCAATGC

[0031] The NOV1 sequence of the invention and all the NOVX sequencesdescribed herein were derived by laboratory cloning of cDNA fragmentscovering the full length and/or part of the DNA sequence of theinvention, and/or by in silico prediction of the full length and/or partof the DNA sequence of the invention from public human sequencedatabases.

[0032] A disclosed NOV1 polypeptide (SEQ ID NO:2) encoded by SEQ ID NO:1has 373 amino acid residues and is presented in Table 1B using theone-letter amino acid code. SignalP, Psort and/or Hydropathy resultspredict that NOV1 has a signal peptide and is likely to be localized tothe plasma membrane. In an alternative embodiment, NOV1 is likely to belocalized to the lysosome (lumen) with a certainty of 0.5500. The mostlikely cleavage site for a NOV1 peptide is between amino acids 17 and18, i.e., at the dash between amino acids LNA-GG. NOV1 has a molecularweight of 42681.4 Daltons. TABLE 1B Encoded NOV1 protein sequence.MWLLLTTTCLICGTLNAGGFLDLENEVNPEVWMNTSEIIIYNGYPSEEYEVTTEDGYILLVNR (SEQ IDNO:2) IPYGRTHARSTGPRPVVYMQHALFADNAYWLENYANGSLGFLLADAGYDVWMGNSRGNTWSRRHKTLSETDEKFWAFGFDEMAKYDLPGVIDFIVNKTGQEKLYFIGHSLGTTIGFVAFSTMPELAQRIKMNFALGPTISFKYPTGIFTRFFLLPNSIIKAVFGTKGFFLEDKKTKIASTKICNNKILWLICSEFMSLWAGSNKKNMNQLYHSDEFRAYDWGNDADNMKHYNQSHPPIYDLTAMKVPTAIWAGGHDVLVTPQDVARILPQIKSLHYFKLLPDWNHFDFVWGLDAPQRMYSEIIALMKAYS

[0033] In all BLAST alignments herein, the “E-value” or “Expect” valueis a numeric indication of the probability that the aligned sequencescould have achieved their similarity to the BLAST query sequence bychance alone, within the database that was searched. The Expect value(E) is a parameter that describes the number of hits one can “expect” tosee just by chance when searching a database of a particular size. Itdecreases exponentially with the Score (S) that is assigned to a matchbetween two sequences. Essentially, the E value describes the randombackground noise that exists for matches between sequences.

[0034] The Expect value is used as a convenient way to create asignificance threshold for reporting results. The default value used forblasting is typically set to 0.0001, with the filter to remove lowcomplexity sequence turned off. In BLAST 2.0, the Expect value is alsoused instead of the P value (probability) to report the significance ofmatches. For example, an E value of one assigned to a hit can beinterpreted as meaning that in a database of the current size one mightexpect to see one match with a similar score simply by chance. An Evalue of zero means that one would not expect to see any matches with asimilar score simply by chance. See, e.g.,http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/. Occasionally, a stringof X's or N's will result from a BLAST search. This is a result ofautomatic filtering of the query for low-complexity sequence that isperformed to prevent artifactual hits The filter substitutes anylow-complexity sequence that it finds with the letter “N” in nucleotidesequence (e.g., “NNNNNNNN”) or the letter “X” in protein sequences(e.g., “XXX”). Low-complexity regions can result in high scores thatreflect compositional bias rather than significant position-by-positionalignment. Wootton and Federhen, Methods Enzymol 266:554-571, (1996).

[0035] In a search of sequence databases, it was found, for example,that the amino acid sequence of this invention has 154 of 297 bases(51%) identical to a ptnr:SPTREMBL-ACC:Q16529 LYSOSOMAL ACID LIPASEPRECURSOR—Homo sapiens.

[0036] In a further search of public sequence databases, NOV1 was foundto have homology to the amino acid sequences shown in the BLASTP datalisted in Table 1C. TABLE 1C BLASTP results for NOV1 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expect ptnr:SPTREMBL- LYSOSOMAL ACID LIPASE 399 154/297 202/297 7.2e−109 ACC: Q16529PRECURSOR - Homo (51%) (68%) sapiens ptnr: pir-id: S41408 lysosomal acidlipase (EC 399 154/297 202/297 1.2e−108 3.1.1.-)/sterol esterase (51%)(68%) (EC 3.1.1.13) precursor - human ptnr: SWISSPROT- Lysosomal acid399 153/297 201/297 5.1e−108 ACC: P38571 lipase/cholesteryl ester (51%)(67%) hydrolase precursor (EC 3.1.1.13) (LAL) (Acid cholesteryl esterhydrolase) (Sterol esterase) (Lipase A) (Cholesteryl esterase) - Homosapiens ptnr: SPTREMBL- SIMILAR TO LIPASE A, 399 152/297 201/2971.0e−107 ACC: Q96EJ0 LYSOSOMAL ACID, (51%) (67%) CHOLESTEROL ESTERASE(WOLMAN DISEASE) - Homo sapiens ptnr: SWISSPROT- Triacylglycerol lipase,398 146/297 196/297 5.8e−105 ACC: P07098 gastric precursor (EC (49%)(65%) 3.1.1.3) (Gastric lipase) (GL) - Homo sapiens

[0037] The homology of these sequences is shown graphically in theClustalW analysis shown in Table ID. In the ClustalW alignment of theNOV1 protein, as well as all other ClustalW analyses herein, the blackoutlined amino acid residues indicate regions of conserved sequence(i.e., regions that may be required to preserve structural or functionalproperties), whereas non-highlighted amino acid residues are lessconserved and can potentially be mutated to a much broader extentwithout altering protein structure or function. NOV1 polypeptide isprovided in lane 1.

[0038] BLAST analysis was performed on sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 1E. TABLE 1E Patp BLASTP Analysis for NOV1 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp: AAB66061 Human lysosomal acid 399 153/297201/297 3.9e−108 lipase protein - Homo (51%) (67%) sapiens patp:AAB90783 Human shear stress- 399 153/297 201/297 3.9e−108 responseprotein SEQ ID (51%) (67%) NO: 66 - Homo sapiens patp: AAP60724 Sequenceof pregastric 398 146/297 196/297 4.5e−105 lipase - Homo sapiens (49%)(65%) patp: AAP60658 Sequence of human 398 146/297 196/297 4.5e−105pregastric lipase - Homo (49%) (65%) sapiens patp: AAW09383 Humangastric lipase 398 146/297 196/297 4.5e−105 protein sequence - Homosapiens (49%) (65%)

[0039] The presence of identifiable domains in NOV1, as well as allother NOVX proteins, was determined by searches using softwarealgorithms such as PROSITE, DOMAIN, Blocks, Pfam, ProDomain, and Prints,and then determining the Interpro number by crossing the domain match(or numbers) using the Interpro website (http:www.ebi.ac.uk/interpro).DOMAIN results for NOV1 as disclosed in Tables 1F, were collected fromthe Conserved Domain Database (CDD) with Reverse Position Specific BLASTanalyses. This BLAST analysis software samples domains found in theSmart and Pfam collections.

[0040] Table 1F lists the domain description from DOMAIN analysisresults against NOV1. This indicates that the NOV1 sequence hasproperties similar to those of other proteins known to contain thesedomains. For Table 1F and all successive DOMAIN sequence alignments,fully conserved single residues are indicated by black shading or by thesign (|) and “strong” semi-conserved residues are indicated by greyshading or by the sign (+). In a sequence alignment herein, fullyconserved single residues are calculated to determine percent homology,and conserved and “strong” semi-conserved residues are calculated todetermine percent positives. The “strong” group of conserved amino acidresidues may be any one of the following groups of amino acids: STA,NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW. TABLE 1F Domain Analysis ofNOV1 PSSMs producing significant alignments: Score (bits) Evalueabbydrolase alpha/beta hydrolase fold 64.8 1.8e−15 Parsed for domains:Model Domain seq-f seq-t hmm-f hmm-t score E-value abhydrolase 1/1 111366 .. 1 232[ ] 64.8 1.8e-15 Alignments of top-scoring domains:abhydrolase: domain 1 of 1, from 111 to 366frvillDlrGfGeSsp.............sdlaeyrfddlaedleal (SEQ ID NO:66)++|++++ ||  +|+++++ ++++++     ++|    ||   ++ + NOV1 111YDVWMGNSRGNTWSRRhktlsetdekfwaFGFDEMAKYDLPGVIDFI 157ldalglekpvilvGhSmGGaialayaakyPel..rvkalvlvspp..... +++|+|| ++ +|||+|++|++ + ++ ||| +|+|+  +++|  + +  158VNKTGQEK-LYFIGHSLGTTIGFVAFSTMPELaqRIKNNFALGPTisfky 206......lpaglssdlfprqgnleglllanfrnrlsrsveallgralkqff+++  + +++|++ ++++  +++|++|+          ++  ++++  ++ 207ptgiftRFFLLPNSIIKAVFGTKGFFLEDKKT--KIASTKICNNKI--LW 252llgrplvsdflkqaedwlsslirqgeddggdgllgaavalgkllqwdls.| +++++|   +  +++ ++|++  | +++|+++ |++ + ++++ +++ 253LICSEFMSLWAGSNKKNMNQLYHSDEFRAYDWCNDADNMKHYNQSHPPIy 302alkdikvPtlviwgtdDplvpldaseklsalipn.aevvviddagHlall+|+ +|||| ++ |++| ||+++++ ++   |++ + +++++|+ |+ +  303DLTAMKVPTAIWAGGHDVLVTPQDVARILPQIKSlHYFKLLPDWNHFDFV 352 ekpeevaeli.kfl<-*++ ++  +++++ 353 WGLDAPQRMYsEII 366

[0041] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies.

[0042] NOV2

[0043] A disclosed NOV2 nucleic acid (SEQ ID NO:3) of 12348 nucleotides(also referred to as 20708613_EXT1) encoding a novelMEGF/FLAMINGO/Cadherin-like protein is shown in Table 2A. An openreading frame was identified beginning with an ATG initiation codon atnucleotides 1-3 and ending with a TGA codon at nucleotides 12346-12348.The start and stop codons are shown in bold letters in Table 2A. TABLE2A NOV2 nucleotide sequence.ATGGCGAGGCGGCCGCCGTGGCGGGGCCTCGGGGAACGGTCGACCCCCATACTCCTGCTCCTTC (SEQ IDNO:3) TCCTCTCTTTGTTCCCCCTCAGCCAGGAGGAGCTGGGGGGCGGTGGGCACCAGGGCTGGGACCCAGGCTTAGCTGCCACTACGGGGCCAAGGGCGCATATCGGTGGCGGAGCCTTAGCTCTTTGTCCGGAGTCTTCCGGGGTCCGGGAGGATGGGGGGCCTGGCCTGGGGGTCAGGGAGCCTATCTTCGTGGGGCTCCGAGGGAGAAGGCAAAGCGCCCGGAATAGTCGAGGGCCCCCTGAGCAGCCGAATGAGGAGCTGGGGATTGAACACGGCGTCCAGCCATTGGGCAGCCGCGAACGAGAGACAGGACAGGGACCAGGGTCTGTGTTATACTGGCGCCCAGAGGTCTCCTCTTGCGGGCGGACAGGACCTTTGCAAAGAGGTAGTCTGTCACCAGGGGCTCTGTCCTCAGGGGTCCCGGGCTCGGGGAACAGCTCGCCCCTCCCTTCAGACTTTTTGATTCGGCACCACGGTCCCAAGCCGGTGTCCTCCCAGCGGAACGCTGGGACAGGCTCCCGCAAAAGAGTGGGCACCGCGCGCTGCTGTGGGGAATTATGGGCAACAGGGAGCAAGGGTCAGGGCGAGAGAGCCACGACATCCGGAGCAGAAAGGACAGCCCCCCGGCGGAACTGTCTTCCAGGGGCCTCGGGATCTGGCCCCGAGCTGGATTCAGCACCACGCACGGCGAGGACAGCTCCTGCATCAGGTTCAGCACCCCGCGAGTCTCGGACAGCTCCCGAGCCGGCGCCCAAGCGCATGCGCTCCCGGGGTCTCTTCCGCTGCCGCTTCCTCCCGCAGCGCCCCGGGCCGCGTCCCCCGGGACTCCCGGCCCGTCCTGAAGCCAGGAAAGTAACCTCGGCGAACCGGGCACGCTTTCGTCGCGCCGCAAACCGCCACCCGCAGTTTCCGCAGTACAACTACCAGACGCTGGTGCCGGAGAATGAGGCAGCAGGCACCGCGGTGCTACGCGTGGTTGCTCAGGACCCGGACGCCGGCGAGGCCGGGCGCCTAGTCTACTCGCTGGCGGCACTCATGAACAGCCGCTCGCTGGAGCTGTTCAGCATCGACCCGCAGAGCGGCCTTATCCGTACGGCGGCAGCTCTGGACCGCGAGAGCATGGAGCGTCACTACCTGCGTGTGACCGCGCAGGACCACGGGTCGCCGCGCCTCTCGGCCACCACGATGGTGGCCGTGACAGTAGCCGACCGCAACGACCACTCGCCGGTTTTTGAGCAAGCGCAGTACCGGGAGACCCTTCGCGAGAATGTGGAGGAGGGCTACCCTATCCTGCAGCTGCGTGCCACTGACGGCGACGCGCCCCCCAACGCCAACCTGCGCTACCGCTTCGTGGGGCCGCCAGCTGCGCGCGCTGCAGCTGCCGCCGCCTTCGAGATTGATCCACGCTCCGGCCTCATCAGCACCAGCGGCCGAGTGGACCGCGAGCACATGGAAAGCTATGAGCTGGTGGTGGAAGCCAGCGACCAGGGCCAGGAACCCGGGCCGCGCTCGGCCACTGTGCGCGTACACATAACTGTGCTAGACGAGAACGACAATGCTCCTCAGTTCAGCGAGAAGCGCTACGTGGCGCAGGTGCGCGAGGATGTGCGCCCCCACACAGTCGTGCTGCGCGTCACGGCCACTGACCGGGACAAGGACGCCAACGGATTGGTGCACTACAACATCATCAGTGGCAATAGCCGTGGACACTTTGCCATCGACAGCCTCACTGGCGAGATCCAGGTGGTGGCACCTCTGGACTTCGAGGCAGAGAGAGAGTATGCCTTGCGCATCAGGGCGCAGGATGCTGGCCGGCCACCGCTGTCCAACAACACGGGCCTGGCCAGCATCCAGGTGGTGGACATCAATGACCACATTCCTATTTTTGTCAGCACGCCCTTCCAAGTTTCTGTCTTGGAAAATGCTCCCTTGGGTCACTCAGTCATCCACATTCAGGCAGTCGATGCAGACCATGGGGAGAATGCCAGATTGGAGTACTCCCTAACTGGTGTGGCACCTGATACTCCTTTTGTGATAAACAGCGCCACTGGCTGGGTCTCTGTGAGTGGTCCCCTGGACCGTGAGTCTGTGGAGCATTACTTCTTTGGTGTGGAGGCTCGAGACCATGGCTCACCCCCACTCTCTGCCTCAGCCAGTGTCACCGTGACTGTGCTGGACGTTAATGACAATCGGCCTGAGTTCACAATGAAGGAGTACCACCTACGACTGAATGAGGATGCAGCTGTGGGCACCAGTGTGGTCAGCGTGACCGCAGTAGACCGTGATGCCAACAGTGCCATCAGCTACCAGATCACAGGCGGCAACACCCGGAATCGCTTTGCCATCAGCACCCAGGGGGGTGTGGGTCTGGTGACTCTGGCTCTGCCACTGGACTACAAGCAGGAACGCTACTTCAAGCTGGTACTAACTGCATCTGACCGTGCCCTTCATGATCACTGCTATGTGCACATCAACATCACAGATGCCAACACTCATCGGCCGGTCTTTCAAAGTGCCCACTACTCAGTGAGTGTGAATGAAGATCGGCCAATGGGTAGCACCATAGTGGTCATCAGTGCCTCTGATGATGACGTGGGTGAGAATGCTCGTATCACCTATCTCCTGGAGGACAACCTGCCCCAGTTCCGCATTGATGCAGACTCAGGAGCCATTACATTACAGGCCCCATTAGACTATGAGGACCAGGTGACCTACACCCTGGCTATCACAGCTCGGGACAATGGCATCCCACAGAAGGCAGACACTACTTATGTGGAGGTGATGGTCAATGACGTGAATGACAATGCTCCACAATTTGTGGCCTCCCACTATACAGGGCTGGTCTCTGAGGATGCCCCACCTTTCACCAGTGTCCTGCAGATCTCAGCCACTGACCGGGATGCTCATGCCAATGGCCGGGTCCAGTACACTTTCCAGAATGGTGAAGATGGGGATGGAGATTTTACCATTGAGCCCACCTCTGGAATTGTCCGTACAGTAAGGCGGCTAGACCGGGAGGCAGTATCAGTGTATGAGTTGACTGCCTACGCAGTGGACAGAGGTGTGCCCCCACTCCGGACTCCAGTCAGTATCCAGGTGATGGTGCAGGATGTGAACGACAATGCACCTGTCTTCCCAGCTGAGGAGTTTGAGGTGCGGGTGAAAGAGAATAGCATTGTGGGCTCAGTGGTGGCCCAGATCACTGCAGTGGACCCTGACGAAGGCCCCAATGCCCATATAATGTACCAGATCGTGGAGGGGAACATCCCTGAGCTGTTCCAAATGGACATCTTCTCTGGAGAACTGACGGCACTCATTGACCTAGACTATGAGGCTCGCCAAGAATATGTGATTGTGGTGCAGGCCACATCTGCTCCTTTGGTCAGCCGGGCCACTGTGCACGTCCGCCTGGTTGACCAGAATGACAACAGCCCTGTGCTCAACAACTTCCAGATCCTCTTCAACAACTATGTATCCAACCGTTCAGACACCTTCCCGTCGGGCATTATTGGGCGCATCCCAGCTTATGACCCCGATGTCTCCGACCACCTCTTCTACTCCTTTGAGCGTGGCAATGAGCTGCAGCTGCTGGTAGTCAACCAGACCAGTGGGGAGCTGCGACTCAGCCGAAAGCTAGACAATAACCGCCCACTGGTGGCCTCCATGTTGGTGACTGTCACAGATGGCCTGCACAGCGTGACGGCGCAGTGTGTGCTGCGCGTGGTCATCATCACGGAGGAGTTGCTGGCCAACAGCCTGACCGTGCGCCTTGAGAACATGTGGCAGGAGCGCTTCCTGTCACCGCTGCTGGGCCGCTTCCTCGAGGGCGTGGCTGCGGTGCTCGCTACGCCCGCTGAGGACGTCTTCATCTTCAACATCCAGAACGACACAGACGTAGGGGGCACCGTGCTCAATGTGAGTTTCTCGGCGCTAGCTCCACGTGGGGCCGGGGCGGGCGCTGCAGGGCCCTGGTTCAGCTCCGAGGAGCTGCAGGAGCAGTTGTACGTGCGCCGGGCGGCGCTGGCGGCTCGCTCCCTGCTCGACGTACTGCCCTTCGACGACAACGTGTGCCTGCGAGAGCCCTGTGAGAACTACATGAAATGCGTGTCCGTGCTCCGCTTTGACTCGTCCGCGCCCTTCCTGGCCTCGGCCTCCACGCTGTTCCGACCCATCCAGCCCATCGCTGGCCTGCGCTGCCGCTGCCCGCCCGGATTCACGGGAGACTTTTGCGAGACCGAGCTCGACCTCTGCTACTCCAACCCATGTCGCAACGGCGGAGCCTGCGCGCGGCGCGAGGGAGGCTACACGTGCGTCTGCCGCCCGCGCTTCACCGGAGAGGACTGCGAGCTGGACACCGAGGCCGGCCGCTGCGTGCCGGGCGTCTGCCGCAACGGGGGCACCTGCACCGACGCGCCCAACGGCGGCTTTCGCTGCCAGTGCCCGGCAGGCGGCGCCTTCGAGGGCCCGCGCTGCGAGGTGGCTGCGCGCTCCTTCCCGCCCAGTTCGTTCGTCATGTTTCGCGGCCTGCGGCAGCGATTCCACCTTACGCTGTCCCTCTCGTTCGCGACAGTGCAGCAGAGCGGGCTGCTCTTCTACAACGGGCGCCTGAACGAGAAGCACGACTTCCTGGCCCTGGAACTCGTGGCTGGCCAAGTGCGGCTCACATATTCCACGGGTGAATCCAACACCGTGGTCAGCCCCACAGTTCCAGGGGGCTTGAGTGACGGGCAATGGCATACAGTGCATCTCAGATACTACAACAAGCCCCGGACAGATGCCCTAGGGGGTGCACAGGGCCCCTCCAAGGACAAGGTGGCTGTGCTAAGCGTGGATGATTGTGATGTGGCCGTGGCTCTGCAGTTTGGTGCTGAGATTGGCAACTACTCATGCGCGGCTGCTGGTGTGCAAACAAGCTCCAAGAAGTCCCTGGACCTGACGGGCCCTCTTCTTCTGGGAGGTGTCCCCAACCTCCCCGAGAACTTCCCCGTATCCCATAAGGACTTCATCGGCTGTATGCGGGACCTGCACATTGATGGCCGCCCAGTGGACATGGCGGCTTTTGTCGCAAATAATGGCACCATGGCAGGCTGCCAAGCCAAGCTACACTTTTGTGACTCAGGCCCCTGCAAGAACAGTGGCTTCTGCTCGGAGCGCTGGGGCAGCTTCAGCTGCGACTGCCCTGTGGGCTTCGGCGGCAAAGACTGTCAGCTTACTATGGCCCATCCCCACCATTTCCGTGGCAACGGCACACTGAGCTGGAACTTTGGAAGTGACATGGCTGTGTCTGTGCCATGGTACCTGGGGCTGGCATTTCGGACACGGGCAACGCAGGGGGTCCTGATGCAAGTGCAGGCTGGGCCACACAGCACGCTCCTTTGCCAGCTAGATCGGGGGTTACTGTCTGTGACAGTGACCAGGGGCTCGGGCCGTGCTTCCCATCTCCTTCTGGACCAGGTGACTGTCAGTGATGGCCGGTGGCACGATCTGCGGCTGGAGTTGCAGGAGGAACCAGGTGGCCGGCGGGGCCACCATGTCCTTATGGTCTCACTGGACTTTAGCCTCTTCCAGGACACCATGGCGGTGGGGAGTGAGCTGCAGGGCCTGAAGGTAAAGCAGCTCCACGTGGGAGGCCTGCCCCCCGGCAGTGCAGAGGAGGCTCCTCAGGGTCTGGTTGGCTGCATCCAGGGGGTGTGGCTCGGCTCCACACCCTCTGGCTCCCCGGCCCTGCTACCCCCCAGCCACCGAGTGAATGCGGAGCCTGGCTGTGTTGTGACCAACGCCTGTGCCTCTGGGCCCTGCCCACCTCACGCAGACTGCCGGGACCTCTGGCAGACCTTTTCTTGCACCTGCCAGCCAGGTTACTACGGCCCAGGCTGTGTGGATGCCTGCCTCCTGAACCCCTGTCAGAACCAGGGATCATGCCGGCACCTGCCAGGAGCCCCCCATGGCTATACCTGTGACTGTGTGGGTGGCTATTTCGGGCACCACTGTGAGCACAGGATGGACCAGCAGTGCCCACGGGGCTGGTGGGGGAGCCCAACCTGTGGCCCCTGCAACTGTGATGTTCACAAAGGTTTTGATCCCAACTGCAACAAGACAAATGGGCAGTGTCACTGCAAGGAGTTCCACTACCGACCGCGGGGCAGTGACTCTTGCCTCCCATGTGACTGCTACCCTGTGGGCTCCACCTCGCGCTCATGTGCACCCCACAGCGGGCAGTGCCCCTGTCGCCCAGGAGCCCTTGGCCGCCAGTGCAACAGCTGTGACAGTCCCTTCGCAGAGGTGACAGCCAGCGGCTGCCGGGTGCTCTATGATGCCTGCCCTAAGTCCCTGAGATCTGGTGTGTGGTGGCCCCAGACAAAGTTTGGCGTCCTGGCCACAGTGCCCTGTCCCCGGGGGGCCCTGGGTGCTGCTGTGCGGCTGTGTGATGAGGCCCAGGGTTGGCTGGAGCCCGACCTCTTCAACTGTACCTCCCCTGCCTTTCGAGAGCTCAGTCTGCTGCTGGATGGCCTAGAGCTGAACAAGACGGCACTGGATACCATGGAGGCCAAGAAGCTGGCTCAGCGGCTACGGGAGGTGACTGGCCACACTGACCACTATTTTAGCCAAGATGTTCGAGTCACTGCCCGCCTGCTGGCCCACCTGCTGGCCTTCGAGAGCCATCAGCAGGGCTTCGGGCTGACAGCCACACAGGATGCCCACTTCAATGAGAATCTGCTGTGGGCCGGCTCTGCACTGCTTGCCCCAGAGACAGGGGACTTGTGGGCGGCGCTGGGGCAGCGGGCCCCTGGGGGCTCCCCAGGCAGCGCGGGACTGGTGAGGCACCTGGAGGAGTATGCAGCCACACTCGCAAGGAATATGGAACTCACATACCTGAATCCCATGGGGCTGGTGACGCCTAATATCATGCTCAGCATTGACCGCATGGAGCACCCCAGTTCTCCCCGGGGGGCCCGTCGCTACCCTCGCTACCATAGCAACCTCTTTCGAGGCCAGGATGCCTGGGATCCTCACACCCATGTGCTGCTGCCTTCCCAGTCCCCACGGCCATCCCCATCTGAAGTTCTGCCCACAAGCAGCAGCATAGAAAACTCCACCACCTCAAGTGTGGTCCCCCCACCAGCCCCGCCAGAGCCAGAGCCTGGGATCTCCATTATCATTCTCCTCGTTTACCGCACCTTAGGGGGACTGCTCCCTGCCCAGTTCCAGGCAGAACGCCGAGGTGCCAGGCTTCCTCAGAACCCCGTCATGAACTCCCCGGTGGTCAGCGTGGCTGTGTTCCACGGACGCAACTTCCTAAGGGGAATCCTGGAGTCCCCCATCAGCCTAGAGTTTCGCCTGCTACAGACAGCGAATCGGAGCAAGGCGATCTGTGTGCAGTGGGACCCACCTGGCCTGGCGGAGCAGCATGGTGTGTGGACAGCACGGGACTGCGAGCTGGTGCACAGGAATGGGTCCCACGCACGGTGTCGCTGCAGCCGGACAGGGACCTTTGGGGTCCTCATGGATGCCTCTCCCCGTGAGAGGCTGGAGGGCGACCTGGAGCTGCTGGCTGTGTTCACCCACGTGGTCGTGGCTGTGTCTGTGGCTGCGCTGGTGCTGACTGCAGCCATCCTGCTGAGCCTGCGCAGCCTCAAGTCCAATGTGCGTGGGATCCATGCCAATGTGGCAGCCGCCCTGGGGGTGGCAGAGCTCCTCTTCCTGCTGGGGATTCACAGGACCCACAATCAGGTGCAGGATCAGGGCCAGGGAACTTGTGTCCTGATGACCCTACTGGCCCAGGAGGCCTGGGGCCAAAACTCAGGGTCAGAGCTGGTGTGCACTGCAGTCGCCATCCTCCTGCACTACTTCTTCCTCAGCACCTTCGCGTGGCTCTTCGTGCAGGGGCTGCACCTCTACCGCATGCAGGTTGAGCCACGCAACGTGGACCGCGGCGCCATGCGCTTCTACCATGCCCTGGGCTGGGGCGTCCCTGCTGTGCTGCTGGGCCTTGCTGTGGGCCTGGACCCTGAGGGCTATGGGAACCCTGACTTCTGCTGGATCTCAGTCCACGAGCCCCTCATCTGGAGCTTTGCTGGCCCTGTTGTCCTGGTCATAGTGATGAACGGGACCATGTTTCTCCTCGCTGCCCGCACATCCTGCTCCACAGGGCAGAGCGAGGCCAAGAAGACCTCTGCACTCAGGACCCTTCGCAGCTCCTTCCTGCTGCTTCTGCTGGTCAGTGCCTCCTGGCTCTTTGGGCTCCTGGCAGTCAACCACAGCATCCTAGCCTTCCACTACCTCCATGCTGGACTCTGCGGCCTCCAGGGCCTGGCGGTGCTGCTGCTCTTCTGTGTCCTAAATGCAGATGCTCGGGCTGCCTGGATGCCAGCCTGTCTGGGCAGGAAGGCAGCGCCTGAGGAGGCAAGGCCAGCACCTGGGCTGGGACCTGGCGCCTACAACAACACGGCTCTCTTTGAGGAGAGTGGCCTCATCCGCATCACTCTGGGCGCCTCCACCGTCTCCTCTGTGAGCAGTGCCCGCTCCGGCCGGACCCAGGACCAGGACAGCCAGCGGGGCCGCAGCTACCTCAGGGACAATGTCCTGGTTCGACATGGCTCAGCCGCTGACCACACTGACCACAGCCTCCAGGCTCATGCTGGCCCCACTGACCTGGACGTGGCCATGTTCCATCGAGATGCTGGCGCAGACTCCGACTCTGACAGTGACCTGTCCTTGGAGGAGGAGAGGAGTCTCTCCATTCCATCTTCAGAAAGCGAGGACAATGGCCGGACGCGGGGGCGCTTCCAACGGCCACTCTGCCGAGCAGCCCAGAGTGAGAGGCTCCTCACCCACCCCAAAGATGTGGATGGCAATGACCTCCTGTCCTACTGGCCAGCCCTGGGGGAGTGCGAGGCAGCCCCCTGTGCTCTGCAGACTTGGGGCTCTGAAAGGCGCCTGGGGCTGGACACCAGCAAGGATGCAGCTAACAACAACCAGCCAGACCCGGCCCTGACCAGTGGGGATGAGACTTCTCTGGGCCGGGCCCAGCGCCAGAGGAAAGGCATCCTGAAGAACCGGTTGCAATACCCACTGGTGCCACAGACCCGAGGTGCCCCTGAGCTGTCCTGGTGCCGTGCAGCCACCTTGGGCCACCGTGCAGTGCCAGCTGCCTCTTACGGTCGCATCTATGCTGGCGGGGGCACGGGCAGCCTTTCACAGCCAGCCAGCCGCTACTCTTCTAGAGAACAGCTGGACCTGCTCCTCCGGCGGCAACTGAGCCGTGAGCGACTAGAGGAAGCCCCTGCCCCTGTTCTACGTCCCCTGAGCCGGCCAGGGTCCCAGGAATGCATGGATGCTGCACCAGGCCGACTGGAGCCCAAAGATCGGGGCAGCACCCTGCCACGGAGGCAGCCACCTCGGGACTACCCTGGCGCCATGGCTGGCCGCTTCGGGTCACGGGATGCGCTCGACTTAGGGGCACCTCGAGAGTGGTTGAGCACGCTGCCTCCGCCCCGCCGCACCCGGGACCTTGACCCACAGCCCCCACCTCTGCCCCTGTCTCCCCAGCGGCAACTCTCAAGGGACCCCCTCTTGCCATCCCGGCCGCTGGACTCTCTGTCTAGGAGCTCGAACTCTCGGGAGCAGCTGGACCAGGTGCCTAGCCGGCACCCCTCACGAGAAGCCCTTGGGCCACTCCCGCAGCTGCTCAGAGCTAGGGAGGACTCGGTCAGTGGCCCCAGCCATGGCCCCTCCACAGAACAGTTGGACATTCTTTCCTCCATCCTTGCCTCTTTCAACTCCTCGGCCCTCTCCTCTGTGCAATCTTCAAGCACACCCTTGGGCCCTCACACCACTGCCACACCTTCTGCCACAGCCTCTGTGCTTGGGCCCTCCACGCCACGTTCTGCCACGTCTCACAGCATCTCGGAGCTGTCGCCAGACTCAGAACCGAGGGACACACAGGCACTGCTGTCTGCAACACAAGCAATGGACCTGCGGAGGCGAGACTACCACATGGAACGGCCGCTGCTGAACCAGGAGCATTTGGAGGAGCTGGGGCGCTGGGGCTCAGCACCTAGGACCCACCAGTGGCGGACCTGGTTGCAGTGCTCCCGTGCTCGGGCCTATGCCCTTCTGCTCCAACACCTCCCGGTTTTGGTCTGGTTACCCCGGTATCCTGTGCGTGACTGGCTCCTGGGTGACCTGTTATCCGGCCTGAGTGTGGCCATCATGCAGCTTCCGCAGGGCTTGGCCTACGCCCTCCTGGCTGGATTGCCCCCCGTGTTTGGCCTCTATAGCTCCTTCTACCCTGTCTTCATCTACTTCCTGTTTGGCACTTCCCGGCACATCTCCGTGGAGAGCCTCTGTGTCCCGGGACCAGTAGACACAGGGACCTTTGCTGTCATGTCTGTGATGGTGGGCAGTGTGACAGAATCCCTGGCCCCGCAGGCCTTGAACGACTCCATGATCAATGAGACAGCCAGAGATGCTGCCCGGGTACAGGTGGCCTCCACACTCAGTGTCCTGGTTGGCCTCTTCCAGGTGGGGCTGGGCCTGATCCACTTCGGCTTCGTGGTCACCTACCTGTCAGAACCTCTTGTCCGAGGCTATACCACAGCTGCAGCTGTGCAGGTCTTCGTCTCACAGCTCAAGTATGTGTTTGGCCTCCATCTGAGCAGCCACTCTGGGCCACTGTCCCTCATCTATACAGTGCTGGAGGTCTGCTGGAAGCTGCCCCAGAGCAAGGTTGGCACCGTGGTCACTGCAGCTGTGGCTGGGGTGGTGCTCGTGGTGGTGAAGCTGTTGAATGACAAGCTGCAGCAGCAGCTGCCCATGCCGATACCCGGGGAGCTGCTCACGCTCATCGGGGCCACAGGCATCTCCTATGGCATGGGTCTAAAGCACAGATTTGAGGTAGATGTCGTGGGCAACATCCCTGCAGGGCTGGTGCCCCCAGTGGCCCCCAACACCCAGCTGTTCTCAAAGCTCGTGGGCAGCGCCTTCACCATCGCTGTGGTTGGGTTTGCCATTGCCATCTCACTGGGGAAGATCTTCGCCCTGAGGCACGGCTACCGGGTGGACAGCAACCAGGAGCTGGTGGCCCTGGGCCTCAGTAACCTTATCGGAGGCATCTTCCAGTGCTTCCCCGTGAGTTGCTCTATGTCTCGGAGCCTGGTACAGGAGAGCACCGGGGGCAACTCGCAGGTTGCTGGAGCCATCTCTTCCCTTTTCATCCTCCTCATCATTGTCAAACTTGGGGAACTCTTCCATGACCTGCCCAAGGCGGTCCTGGCAGCCATCATCATTGTGAACCTGAAGGGCATGCTGAGGCAGCTCAGCGACATGCGCTCCCTCTGGAAGGCCAATCGGGCGGATCTGCTTATCTGGCTGGTGACCTTCACGGCCACCATCTTGCTGAACCTGGACCTTGGCTTGGTGGTTGCGGTCATCTTCTCCCTGCTGCTCGTGGTGGTCCGGACACAGATGCCCCACTACTCTGTCCTGGGGCAGGTGCCAGACACGGATATTTACAGAGATGTGGCAGAGTACTCAGAGGCCAAGGAAGTCCGGGGGGTGAAGGTCTTCCGCTCCTCGGCCACCGTGTACTTTGCCAATGCTGAGTTCTACAGTGATGCGCTGAAGCAGAGGTGTGGTGTGGATGTCGACTTCCTCATCTCCCAGAAGAAGAAACTGCTCAAGAAGCAGGAGCAGCTGAAGCTGAAGCAACTGCAGAAAGAGGAGAAGCTTCGGAAACAGGCAGGGCCCCTTTTGTCTGCATGTCTGGCTCCCCAGCAGGTGAGCTCAGGAGATAAGATGGAAGATGCAACAGCCAATGGTCAAGAAGACTCCAAGGCCCCAGATGGGTCCACACTGAAGGCCCTGGGCCTGCCTCAGCCAGACTTCCACAGCCTCATCCTGGACCTGGGTGCCCTCTCCTTTGTGGACACTGTGTGCCTCAAGAGCCTGAAGAATATTTTCCATGACTTCCGGGAGATTGAGGTGGAGGTGTACATGGCGGCCTGCCACAGCCCTGTGGTCAGCCAGCTTGAGGCTGGGCACTTCTTCGATGCATCCATCACCAAGAAGCATCTCTTTGCCTCTGTCCATGATGCTGTCACCTTTGCCCTCCAACACCCGAGGCCTGTCCCCGACAGCCCTGTTTCGCCCTCACTCGCTGTCTCCTCAGATGTGAAACAGTTGGAACCAGAGCTGCTTCTCAGGAATAATTTGCTCTCAGGAATACCCGAGAAGGTACAGGGCAGCGTGGGTGCCAATGGGCAGTCCCTGGAGGATACAGAGTGA

[0044] The chromosomal locus for 20708613_EXT1 is 3p21.3-4. Thisinformation was assigned using OMIM, the electronic northernbioinformatic tool implemented by CuraGen Corporation, public ESTs,public literature references and/or genomic clone homologies. This wasexecuted to derive the chromosomal mapping of the SeqCalling assemblies,Genomic clones, literature references and/or EST NOVX sequences that areincluded in the invention.

[0045] In a search of sequence databases, it was found, for example,BlastX analysis of 20708613_EXT1 showed that there was 94% (2449/2599bp) homology to Rattus norvegicus protein MEGF (SPTREMBL-ACC:O88278).MEGF stands for multiple epidermal growth factor repeat containingprotein. 20708613_EXT1 also showed 70% (1684/2384 bp) homology to Musmusculus protein FLAMINGO 1 (TREMBLNEW-ACC: BAA84070).

[0046] A disclosed NOV2 polypeptide (SEQ ID NO:4) encoded by SEQ ID NO:3has 4115 amino acid residues and is presented in Table 2B using theone-letter amino acid code. NOV2 is likely a Type IIIa membrane protein(clv). SignalP, Psort and/or Hydropathy results predict that NOV2 has asignal peptide and is likely to be localized plasma membrane with acertainty of 0.8200. In an alternative embodiment, NOV2 is likely to belocalized to the Golgi body with a certainty of 0.4600, or to theendoplasmic reticulum (membrane) with a certainty of 0.3700, or to theendoplasmic reticulum (lumen) with a certainty of 0.1000. The mostlikely cleavage site for a NOV2 peptide is between amino acids 31 and32, i.e., at the dash between amino acids SQE-EL. TABLE 2B Encoded NOV2protein sequence.MARRPPWRGLGERSTPILLLLLLSLFPLSQEELGGGGHQGWDPGLAATTGPRAHIGGGALALCP (SEQ IDNO:4) ESSGVREDGGPGLGVREPIFVGLRGRRQSARNSRGPPEQPNEELGIEHGVQPLGSRERETGQGPGSVLYWRPEVSSCGRTGPLQRGSLSPGALSSGVPGSGNSSPLPSDFLIRHHGPKPVSSQRNAGTGSRKRVGTARCCGELWATGSKGQGERATTSGAERTAPRRNCLPGASGSGPELDSAPRTARTAPASGSAPRESRTAPEPAPKRMRSRGLFRCRFLPQRPGPRPPGLPARPEARKVTSANRARFRRAANRHPQFPQYNYQTLVPENEAAGTAVLRVVAQDPDAGEAGRLVYSLAALMNSRSLELFSIDPQSGLIRTAAALDRESMERHYLRVTAQDHGSPRLSATTMVAVTVADRNDHSPVFEQAQYRETLRENVEEGYPILQLRATDGDAPPNANLRYRFVGPPAARAAAAAAFEIDPRSGLISTSGRVDREHMESYELVVEASDQGQEPGPRSATVRVHITVLDENDNAPQFSEKRYVAQVREDVRPHTVVLRVTATDRDKDANGLVHYNIISGNSRGHFAIDSLTGEIQVVAPLDFEAEREYALRIRAQDAGRPPLSNNTGLASIQVVDINDHIPIFVSTPFQVSVLENAPLGHSVIHIQAVDADHGENARLEYSLTGVAPDTPFVINSATGWVSVSGPLDRESVEHYFFGVEARDHGSPPLSASASVTVTVLDVNDNRPEFTMKEYHLRLNEDAAVGTSVVSVTAVDRDANSAISYQITGGNTRNRFAISTQGGVGLVTLALPLDYKQERYFKLVLTASDRALHDHCYVHINITDANTHRPVFQSAHYSVSVNEDRPMGSTIVVISASDDDVGENARITYLLEDNLPQFRIDADSGAITLQAPLDYEDQVTYTLAITARDNGIPQKADTTYVEVMVNDVNDNAPQFVASHYTGLVSEDAPPFTSVLQISATDRDAHANGRVQYTFQNGEDGDGDFTIEPTSGIVRTVRRLDREAVSVYELTAYAVDRGVPPLRTPVSIQVMVQDVNDNAPVFPAEEFEVRVKENSIVGSVVAQITAVDPDEGPNAHIMYQIVEGNIPELFQMDIFSGELTALIDLDYEARQEYVIVVQATSAPLVSRATVHVRLVDQNDNSPVLNNFQILFNNYVSNRSDTFPSGIIGRIPAYDPDVSDHLFYSFERGNELQLLVVNQTSGELRLSRKLDNNRPLVASMLVTVTDGLHSVTAQCVLRVVIITEELLANSLTVRLENMWQERFLSPLLGRFLEGVAAVLATPAEDVFIFNIQNDTDVGGTVLNVSFSALAPRGAGAGAAGPWFSSEELQEQLYVRRAALAARSLLDVLPFDDNVCLREPCENYMKCVSVLRFDSSAPFLASASTLFRPIQPIAGLRCRCPPGFTGDFCETELDLCYSNPCRNGGACARREGGYTCVCRPRFTGEDCELDTEAGRCVPGVCRNGGTCTDAPNGGFRCQCPAGGAFEGPRCEVAARSFPPSSFVMFRGLRQRFHLTLSLSFATVQQSGLLFYNGRLNEKHDFLALELVAGQVRLTYSTGESNTVVSPTVPGGLSDGQWHTVHLRYYNKPRTDALGGAQGPSKDKVAVLSVDDCDVAVALQFGAEIGNYSCAAAGVQTSSKKSLDLTGPLLLGGVPNLPENFPVSHKDFIGCMRDLHIDGRRVDMAAFVANNGTMAGCQAKLHFCDSGPCKNSGFCSERWGSFSCDCPVGFGGKDCQLTMAHPHHFRGNGTLSWNFGSDMAVSVPWYLGLAFRTRATQGVLMQVQAGPHSTLLCQLDRGLLSVTVTRGSGRASHLLLDQVTVSDGRWHDLRLELQEEPGGRRGHHVLMVSLDFSLFQDTMAVGSELQGLKVKQLHVGGLPPGSAEEAPQGLVGCIQGVWLGSTPSGSPALLPPSHRVNAEPGCVVTNACASGPCPPHADCRDLWQTFSCTCQPGYYGPGCVDACLLNPCQNQGSCRHLPGAPHGYTCDCVGGYFGHHCEHRMDQQCPRGWWGSPTCGPCNCDVHKGFDPNCNKTNGQCHCKEFHYRPRGSDSCLPCDCYPVGSTSRSCAPHSGQCPCRPGALGRQCNSCDSPFAEVTASGCRVLYDACPKSLRSGVWWPQTKFGVLATVPCPRGALGAAVRLCDEAQGWLEPDLFNCTSPAFRELSLLLDGLELNKTALDTMEAKKLAQRLREVTGHTDHYFSQDVRVTARLLAHLLAFESHQQGFGLTATQDAHFNENLLWAGSALLAPETGDLWAALGQRAPGGSPGSAGLVRHLEEYAATLARNMELTYLNPMGLVTPNIMLSIDRMEHPSSPRGARRYPRYHSNLFRGQDAWDPHTHVLLPSQSPRPSPSEVLPTSSSIENSTTSSVVPPPAPPEPEPGISIIILLVYRTLGGLLPAQFQAERRGARLPQNPVMNSPVVSVAVFHGRNFLRGILESPISLEFRLLQTANRSKAICVQWDPPGLAEQHGVWTARDCELVHRNGSHARCRCSRTGTFGVLMDASPRERLEGDLELLAVFTHVVVAVSVAALVLTAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQVQDQGQGTCVLMTLLAQEAWGQNSGSELVCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMRFYHALGWGVPAVLLGLAVGLDPEGYGNPDFCWISVHEPLIWSFAGPVVLVIVMNGTMFLLAARTSCSTGQREAKKTSALRTLRSSFLLLLLVSASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADARAAWMPACLGRKAAPEEARPAPGLGPGAYNNTALFEESGLIRITLGASTVSSVSSARSGRTQDQDSQRGRSYLRDNVLVRHGSAADHTDHSLQAHAGPTDLDVAMFHRDAGADSDSDSDLSLEEERSLSIPSSESEDNGRTRGRFQRPLCRAAQSERLLTHPKDVDGNDLLSYWPALGECEAAPCALQTWGSERRLGLDTSKDAANNNQPDPALTSGDETSLGRAQRQRKGILKNRLQYPLVPQTRGAPELSWCRAATLGHRAVPAASYGRIYAGGGTGSLSQPASRYSSREQLDLLLRRQLSRERLEEAPAPVLRPLSRPGSQECMDAAPGRLEPKDRGSTLPRRQPPRDYPGAMAGRFGSRDALDLGAPREWLSTLPPPRRTRDLDPQPPPLPLSPQRQLSRDPLLPSRPLDSLSRSSNSREQLDQVPSRHPSREALGPLPQLLRAREDSVSGPSHGPSTEQLDILSSILASFNSSALSSVQSSSTPLGPHTTATPSATASVLGPSTPRSATSHSISELSPDSEPRDTQALLSATQAMDLRRRDYHMERPLLNQEHLEELGRWGSAPRTHQWRTWLQCSRARAYALLLQHLPVLVWLPRYPVRDWLLGDLLSGLSVAIMQLPQGLAYALLAGLPPVFGLYSSFYPVFIYFLFGTSRHISVESLCVPGPVDTGTFAVMSVMVGSVTESLAPQALNDSMINETARDAARVQVASTLSVLVGLFQVGLGLIHFGFVVTYLSEPLVRGYTTAAAVQVFVSQLKYVFGLHLSSHSGPLSLIYTVLEVCWKLPQSKVGTVVTAAVAGVVLVVVKLLNDKLQQQLPMPIPGELLTLIGATGISYGMGLKHRFEVDVVGNIPAGLVPPVAPNTQLFSKLVGSAFTIAVVGFAIAISLGKIFALRHGYRVDSNQELVALGLSNLIGGIFQCFPVSCSMSRSLVQESTGGNSQVAGAISSLFILLIIVKLGELFHDLPKAVLAAIIIVNLKGMLRQLSDMRSLWKANRADLLIWLVTFTATILLNLDLGLVVAVIFSLLLVVVRTQMPHYSVLGQVPDTDIYRDVAEYSEAKEVRGVKVFRSSATVYFANAEFYSDALKQRCGVDVDFLISQKKKLLKKQEQLKLKQLQKEEKLRKQAGPLLSACLAPQQVSSGDKMEDATANGQEDSKAPDGSTLKALGLPQPDFHSLILDLGALSFVDTVCLKSLKNIFHDFREIEVEVYMAACHSPVVSQLEAGHFFDASITKKHLFASVHDAVTFALQHPRPVPDSPVSPSLAVSSDVKQLEPELLLRNNLLSGIPEKVQGSVGANGQSLEDTE

[0047] The full amino acid sequence of the protein of the invention wasfound to have 2376 of 2599 amino acid residues (91%) identical to, and2449 of 2599 residues (94%) positive with, the amino acid residueprotein from Rattus norvegicus ptnr: SPTREMBL-ACC:O88278 MEGF2.

[0048] In a further search of public sequence databases, NOV2 was foundto have homology to the amino acid sequences shown in the BLASTP datalisted in Table 2C. TABLE 2C BLASTP results for NOV2 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expect ptnr:SPTREMBL- PROTOCADHERIN FLAMINGO 3312 2601/2618 2604/2618 0.0 ACC:Q9NYQ7 1 - Homo sapiens (99%) (99%) ptnr: SPTREMBL- CADHERIN EGF LAGSEVEN- 3301 2392/2618 2469/2618 0.0 ACC: Q91ZI0 PASS G-TYPE RECEPTOR -(91%) (94%) Mus musculus ptnr: SPTREMBL- MEGF2 - Rattus norvegicus 33132376/2599 2449/2599 0.0 ACC: O88278 (91%) (94%) ptnr: SPTREMBL- FLAMINGO1 - Homo sapiens 2923 1345/2330 1681/2330 0.0 ACC: Q9HCU4 (57%) (72%)ptnr: SPTREMBL- FLAMINGO 1 - Mus musculus 2920 1348/2384 1684/2384 0.0ACC: Q9R0M0 (56%) (70%)

[0049] The homology of these sequences is shown graphically in theClustalW analysis shown in Table 2D. The NOV2 polypeptide is provided inlane 1.

[0050] BLAST analysis was performed on sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 2E. TABLE 2E Patp BLASTP Analysis for NOV2 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp: AAE03657 Human extracellular matrix 32982421/2618 2450/2618 0.0 and cell adhesion (92%) (93%) molecule-21(XMAD-21) - Homo sapiens patp: AAU07054 Human Flamingo protein 29231345/2330 1681/2330 0.0 encoded by cDNA splice (57%) (72%) variant -Homo sapiens patp: AAU07053 Human Flamingo 2956 1345/2330 1681/2330 0.0polypeptide - Homo (57%) (72%) sapiens patp: AAE08586 Human NOV7protein - 3028 1192/2237 1551/2237 0.0 Homo sapiens (53%) (69%) patp:AAB42192 Human ORFX ORF1956 2405 1046/1687 1284/1687 0.0 polypeptidesequence SEQ (62%) (76%) ID NO: 3912 - Homo sapiens

[0051] Table 2F lists the domain description from DOMAIN analysisresults against NOV2. TABLE 2F Domain Analysis of NOV2 Model Domainseq-f seq-t hmm-f hmm-t score E-value cadherin 1/9 329  423 .. 1 107[]89.9   5e−23 cadherin 2/9 437  535 .. 1 107[] 94.9 1.6e−24 cadherin 3/9549  641 .. 1 107[] 107.4 2.7e−28 cadherin 4/9 655  746 .. 1 107[] 103.93.2e−27 cadherin 5/9 760  848 .. 1 107[] 76.9 4.3e−19 cadherin 6/9 862 951 .. 1 107[] 80.0 4.7e−20 cadherin 7/9 965 1057 .. 1 107[] 99.75.8e−26 cadherin 8/9 1071 1159 .. 1 107[] 87.4 2.8e−22 EGF 2/6 1438 1469.. 1  45[] 33.3 5.6e−06 EGF 3/6 1478 1512 .. 1  45[] 35.8 9.8e−07laminin_G 1/3 1542 1606 .. 1  77[. 56.1 8.2e−15 EGF 4/6 1725 1756 .. 1 45[] 40.4 4.1e−08 laminin_G 3/3 1792 1926 .. 1 161[] 30.4 1.9e−07 EGF5/6 1949 1980 .. 1  45[] 33.1 6.4e−06 EGF 6/6 1984 2018 .. 1  45[] 35.21.5e−06 HRM 1/1 2125 2182 .. 1  79[] 75.6 1.1e−18 GPS 1/1 2475 2528 .. 1 54[] 85.7 9.4e−22 7tm_2 1/1 2535 2805 .. 1 273[] 320.5  2e−92Sulfate_transp 1/1 3532 3842 .. 1 328[] 363.5  2.3e−105 STAS 1/1 38654053 .. 1 116[] 61.3   2e−14 Alignments of top-scoring domains:cadherin: domain 1 of 9, from 329 to 423: score 89.9, E = 5e-23ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnp...gg (SEQ ID NO:72)|+  ||||++ || ||+| |+|+|   |  ||++||+     +++ NOV2 329YQTLVPENEAAGTAVLRVVAQDPD--AGEAGRLVYSLAALMNsrsLE 373wFrIdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsp |+|||++|     |+|++ ||||++  +++ | | |+|+       ||| 374LFSIDPQSGL----IRTAAALDRESM--ERRYLRVTAQDH-------GSP 410 plsgtatvtitVl<-* ||+|++| +|| 411 RLSATTMVAVTVA 423 cadherin: domain 2 of 9, from 437 to535: score 94.9, E = 1.6e-24ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnp..... (SEQ ID NO:73)|  +++||+  | ++|+++||| |   +||+++||+++|++  + NOV2 437YRETLRENVEEGYPILQLRATDGD--APPNANLRYRFVGPPAaraaa 481ggwFrldpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaagg+  |+|||++|     |||  ++|||++  ++|||+|||+|+++ 482AAAFEIDPRSGL----ISTSGRVDREHM--ESYELVVEASDQGQ-----E 520spplsgtatvtitVl<- * ++ |+|+|++|+|||| 521 PGPRSATVRVHITVL 535 cadherin:domain 3 of 9, from 549 to 641: score 107.4, E = 2.7e-28ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnpggwFr (SEQ ID NO:74)|+|+|+|++++ | ||+|||||+|    +|| ++| |++||++|+|+ NOV2 549YVAQVREDVRPHTVVLRVTATDRD--KDANGLVHYNIISGNSRGHFA 593IdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsppls||+ ||+    | +++||| |+   +|| + ||+|++       | |||| 594IDSLTGE----IQVVAPLDFEAE--REYALRIRAQDA-------GRPPLS 630 .gtatvtitVl<-*++|+   |+| 631 nNTGLASIQVV 641 cadherin: domain 4 of 9, from 655 to 746:score 103.9, E = 3.2e-27 ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnpggwFr(SEQ ID NO:75) +++|| |||| | +|++++|+|||  +| |+|+ ||++|  |+  | NOV2 655FQVSVLENAPLGHSVIHIQAVDAD--HGENARLEYSLTGVAPDTPFV 699IdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsppls|+++||+    +|+  |||||+   + | + |||+|+       |||||| 700INSATGW----VSVSGPLDRESV--EEYFFGVEARDH-------GSPPLS 736 gtatvtitVl<-*+ |+||+||| 737 ASASVTVTVL 746 cadherin: domain 5 of 9, from 760 to 848:score 76.9, E = 4.3e-19 ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnpggwFr(SEQ ID NO:76) |+ ++ |+|+|||+| +|||+|+|    +|+ |+| +|+++ || |+ NOV2 760YHLRLNEDAAVGTSVVSVTAVDRD----ANSAISYQITGGNTRNRFA 802IdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsppls| ++ |+  |+++++ |||+ +   + + |++ |+|+          |+ 803ISTQGGV--GLVTLALPLDYKQE--RYFKLVLTASDR----------ALH 838 gtatvtitVl<-*+ ++|+|+++ 839 DECYVHINIT 848 cadlierin: domain 6 of 9, from 862 to 951:score 80.0, E = 4.7e-20 ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnpggwFr(SEQ ID NO:77) ||+|| |+ | |+++ ++ |+| |   | |+||+| +|++|   +|| NOV2 862YSVSVNEDRPMGSTIVVISASDDD--VGENARITY-LLEDN-LPQFR 904IdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsppls|| |+|     |++++|||+| +   +|+| + |+|+       | | + 905IDADSGA----ITLQAPLDYEDQ--VTYTLAITARDN-------GIPQKA 941 gtatvtitVl<-*+|++| + | 942 DTTYVEVMVN 951 cadherin: domain 7 of 9, from 965 to 1057:score 99.7, E = 5.8e-26 ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnp.ggwF(SEQ ID NO:78) |++ |+|+||+ |+||++ |||+|    +|||+ | + +|+ ++| | NOV2 965YTGLVSEDAPPFTSVLQISATDRD--AEANGRVQYTFQNGEDgDGDF 1009rIdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsppl+|+| +|     ++|+++||||+   + |||| +|+|+       | ||| 1010TIEPTSGI----VRTVRRLDREAV--SVYELTAYAVDR-------GVPPL 1046 sgtatvtitVl<-*++++++ + |+ 1047 RTPVSIQVMVQ 1057 cadherin: domain 8 of 9, from 1071 to1159: score 87.4, E = 2.8e-22ysasvpEnapvGtevltvtAtDaDdplgpNgrirYsilggnpggwFr (SEQ ID NO:79)++++|+||+ ||+ |+++||+|+|  +|||+ | | |++|| +  | NOV2 1071FEVRVKENSIVGSVVAQITAVDPD--EGPNAHIMYQIVEGNIPELFQ 1115IdpdtGdnegiisttkpLDREeifngeYeLtveAtDadplsaaggsppls+|  +|+    ++    ||+|++  +||+++| || |          || 1116MDIFSGE----LTALIDLDYEAR--QEYVIVVQATSA----------PLV 1149 gtatvtitVl<-*++|||++ + 1150 SRATVHVRLV 1159 EGF: domain 2 of 6, from 1438 to 1469:score 33.3, E = 5.6e-06 CapnnpcsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-(SEQ ID NO:80) | +| || ||| |   +|       ||||+| |      +||++| NOV2 1438CYSN-PCRNGGACARREG-------GYTCVCRPR-----FTGEDC 1469 EGF: domain 3 of 6,from 1478 to 1512: score 35.8, E = 9.8e-07CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<- (SEQ ID NO:81)| |+ +| |||||++ |+      ||++|+|| |    ++ |+|| NOV2 1478CVPG-VCRNGGTCTDAPN------GGFRCQCPAG---GAFEGPRC 1512 laminin_G: domain 1of 3, from 1542 to 1606: score 56.1, E = 8.2e-15FRTtepsGlLllgYggtntdrggkkeigdDFlaleLvdGrlevsydl (SEQ ID NO:82)|+| ++||||+  |+|  +++        |||||||| |+++++|++ NOV2 1542FATVQQSGLLF--YNGRLNEKH-------DFLALELVAGQVRLTYST 1579GsghrlrpavvrsgdrvlnDGkWHrveler<-* |     + ++ ++++  |+||+||+|+|++ 1580GESN--TVVSPTVPGG-LSDGQWHTVHLRY 1606 EGF: domain 4 of 6, from 1725 to1756: score 40.4, E = 4.1e-08CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<- (SEQ ID NO:83)|+++ ||+| |+| + +|       +++|+||+|     + ||+| NOV2 1725CDSG-PCKNSGFCSERWG-------SFSCDCPVG-----FGGKDC 1756 laminin_G: domain 3of 3, from 1792 to 1926: score 30.4, E = 1.9e-07FRTtepsGlLllgYggtntdrggkkeigdDFlaleLvdGrlevsydl (SEQ ID NO:84)|||++++|+|+     ++  ++         |+ +| +| | |++ NOV2 1792FRTRATQGVLM---QVQAGPHST--------LLCQLDRGLLSVTVTR 1827GsghrlrpavvrsgdrvlnDGkwHrvele........rngrkgtLsVdge|||   |+ ++   + +++||+|| + || +++++++| ++ +++|+| 1828GSG---RASHLLLDQVTVSDGRWHDLRLElqeepggrRGHHVLMVSLDFS 1874epskktlsetvvdgespsgpdvtsenLdldtppityvGGlPeqksvkrrl            + ++ +|++     + |+ + +| |||||  ++ ++++ 1875L----------FQDTMAVGSEL----QGLKVK-QLHVGGLP--PGSAEEA 1907aaistsFkGCirdvsingkpld<-*      +++|||+ |++++ | + 1908---PQGLVGCIQGVNLGSTPSG 1926 EGF: domain 5 of 6, from 1949 to 1980: score33.1, E = 6.4e-06 CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<- (SEQID NO:85) ||++ ||  ++ |+++++       +++|+|+||     | |+ | NOV2 1949CASG-PCPPHADCRDLWQ-------TFSCTCQPG-----YYGPGC 1980 EGF: domain 6 of 6,from 1984 to 2018: score 35.2, E = 1.5e-06CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<- (SEQ ID NO:86)| +| ||+| | |+ +||    + +||||+|  |     | |++| NOV2 1984CLLN-PCQNQGSCRHLPG----APHGYTCDCVGG-----YFGHHC 2018 HRM: domain 1 of 1,from 2125 to 2182: score 75.6, E = 1.1e-18glyCpatwDgilCWPrTpaGtlvvvpCPdyfsGfnydttgedfsngn (SEQ ID NO:87)+++||++   +++||+|++|+|++||||+++ |+ NOV2 2125YDACPKSLRSGVWWPQTKFGVLATVPCPRGALGA------------- 2158asRnCtenGwwerhpnsnwpwpdytnCtspey<-* |+| |+| ++|          ||++||||| +2159 AVRLCDEAQGWL--------EPDLPNCTSPAF 2182 GPS: domain 1 of 1, from 2475to 2528: score 85.7, E = 9.4e-22snpiCvfWdesel..slgvWstdrGCelvetskpshttCsCnHLTsF (SEQ ID NO:88)|++|||+||   | +++|||++ |+||||++++ ||++|+|++ ++| NOV2 2475SKAICVQWDPPGLaeQHGVWTA-RDCELVHRNG-SHARCRCSRTGTF 2519 AvLmdvspn<-*+||||+||+ NOV2 2520 GVLMDASPR 2528 7tm_2: domain 1 of 1, from 2535 to2805: score 320.5, E = 2e-92allLkviytVGyslSsLvcLllaiaifllfRkLrctRnylHmNLfls (SEQ ID NO:89)++|| | ++|++++| +++|+|++||+|++|+|+++   || |  ++ NOV2 2535LELLAVFTHVVVAVS-VAALVLTAAILLSLRSLKSNVRGIHANVAAA 2580fiLralsfLigdavllnsg............................Ckv+ +++|+||+|+++++|+++++++++    +   ++  +++++++  |++ 2581LGVAELLFLLGIHRTHNQVqdqgqgtcvlmtllaqeawgqnsgselvCTA 2630vavflhYfflaNFfWmLvEGlYLytLlvvtvevffserkilwwYlliGWG||++||||||++|+|++| ||+||++    ||+++ +|+ +++|+++||| 2631VAILLHYFFLSTFAWLFVQGLHLYRMQ---VEPRNVDRGAMRFYHALGWG 2677vPavfvtiwaivrpdkygpilaegpagygnegcCWlsndtnsgfwWiikG||||+ +++++++|+           ||||+++||+|   +++++|+++| 2678VPAVLLGLAVGLDPE-----------GYGNPDFCWISV--HEPLIWSFAG 2714PilliilvNfiffinilriLvqKlridslspqtgetdqyrkkrlvkstLl|++|+|++|  +|++++|+ ++  +     +++++|+  |   +++|++| 2715PVVLVIVMNGTMFLLAARTSCSTGQ-----REAKKTSALR---TLRSSFL 2756LlPLLGvtwilflfapedqaqGtlslvflylfliLnSfQGffVavlYCfl||+|+  +|+++|+|+++     + |+|+||+++|+ +||+ | +|+|+| 2757LLLLVSASWLFGLLAVNH-----SILAFHYLHAGLCGLQGLAVLLLFCVL 2801 NgEV<-* | + 2802NADA 2805 Sulfate_transp: domain 1 of 1, from 3532 to 3842: score 363.5,E = 2.3e-105 lGllRLGfLveflSravisGFmaGaAilIllsQLkgllGlsnlftrh (SEQ IDNO:90) |||  +||+|++||++++ |++++||+ +++||||+++||+  +++| NOV2 3532LGLIHFGFVVTYLSEPLVRGYTTAAAVQVFVSQLKYVFGLH--LSSH 3576sgivsvlralfdlvdnlbdflkwnwatlvigisfLifLliikllpnpkkr||+ |++ +++ ++ +|+   + ++ |+|+++++ ++| ++|||+    + 3577SGPLSLIYTVLEVCWKLP---QSKVGTVVTAAVAGVVLVVVKLLN---DK 3620kkklfwvpapapLvavilaTlisylfnrhkladrygvsivGeipsGlppp+   ++ |+|++|+ +|+||+||| +   +|++|+ |++||+|| || || 3621LQQQLPMPIPGELLTLIGATGISYGM---GLKHRFEVDVVGNIPAGLVPP 3667slPrlnlspstlldllpialalAlvgllesiltaksfakikgykiDsNkE  |+++| +++++ ++ |    |+||++ +|+ +| || ++||++|||+| 3668VAPNTQLFSKLVGSAFTI----AVVGFAIAISLGKIFALREGYRVDSNQE 3713LvAqaiaNlvgslfggypatgsfsRSavNvkaGakTqLSgivmavvvllv|||+|++|++|+ | ++|+++| |||+|++++|+++|++| ++++++||+ 3714LVALGLSNLIGGIFQCFPVSCSMSRSLVQESTGGNSQVAGAISSLFILLI 3763lLfltplleyiPmavLaaliivaligmLidwselirllwklsklDfliwl++ |+ |++ +|+|||||||||+|+|||+++|+++  ||| ++ | |||| 3764IVKLGELFHDLPKAVLAAIIIVNLKGMLRQLSDMRS-LWKANRADLLIWL 3812atffgtvfvdNleiGvlvGVaiSllflilrv<-* +||  |+++  |  |++|+|++||| +++|+ 3813VTFTATILLN-LDLGLVVAVIFSLLLVVVRT 3842 STAS: domain 1 of 1, from 3865 to4053: score 61.3, E = 2e-14yieaetipgievlilrlsGpLdfanae.lkerllraiaegperk... (SEQ ID NO:91)| ||++  |+  +++| +| ++|||||   + | + ++ +   ++ NOV2 3865YSEAKEVRGV--KVFRSSATVYFANAEfYSDALKQRCGVD---Vdfl 3906.................................................. +++++  +++++ + ++ +++++ +++ ++  +    +++ +++++ ++ 3907isqkkkllkkqeqlklkqlqkeeklrkqagpllsaclapqqvssgdkmed 3956.......................kielrhvilDlsaVsfiDssGlgaLle + +++++++ +++++ +  + ++++ + +|||| |+||+|+  |  |++ 3957atangqedskapdgstlkalglpQPDFHSLILDLGALSFVDTVCLKSLKN 4006lykelkkrGvelvLvgpspevrrtleltGlddligke.kifptvaeA<-*++++++ + ||++++ ++  |   ||+++++|  + ++++|++|++| 4007IFHDFREIEVEVYMAACHSPVVSQLEAGHFFDASITKkHLFASVHDA 4053

[0052] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients such as Mucopolysaccharidosis type IX;Colorectal cancer, hereditary nonpolyposis, type 2; Turcotsyndrome withglioblastoma, 276300; Muir-Torre family cancer syndrome, 158320;Neurofibromatosis type 1 and leukemia; Hemolytic anemia due toglutathione peroxidase deficiency; Epidermolysis bullosa dystrophica,dominant, 131750; Epidermolysis bullosa dystrophica, recessive, 226600;Epidermolysis bullosa, pretibial, 131850; Metaphyseal chondrodysplasia,Murk Jansen type, 156400; Colorectal cancer; Hepatoblastoma;Pilomatricoma; Ovarian carcinoma, endometrioid type.

[0053] The protein similarity information for the invention(s) suggestthat this gene may function as MEGF, Flamingo or cadherin family genesin the tissues in which it is expressed and in the pathologies in whichit has been implicated (Tissue expression and disease associationsection). Therefore, the nucleic acids and proteins of the invention areuseful in potential therapeutic applications implicated in variouspathologies/disorders described previously and/or otherpathologies/disorders associated with the tissues in which it isexpressed, as well as disorders that MEGF, Flamingo and cadherin familymembers have been implicated. This gene is expressed in the followingtissues: Thalamus, Fetal Brain. Since this protein's transcript wasfound in brain tissue, the gene encoding for it may be implicated in thefollowing (but not limited to) neurodegenerative disorders: Dementia,Amyothrophic Lateral Sclerosis, Alzheimer Disease, Dystonia, OpticAtrophy and Huntington Disease. Additional disease indications andtissue expression for NOV2 and NOV2 variants, if available, arepresented in the Examples.

[0054] Screening exploits 5′-end single-pass sequence data obtained froma pool of cDNAs whose sizes exceed 5 kb. Using this screening procedure,five known and nine new genes for proteins with multiple EGF-like-motifsfrom 8000 redundant human brain cDNA clones were identified. These newgenes were found to encode a novel mammalian homologue of Drosophila fatprotein, two seven-transmembrane proteins containing multiple cadherinand EGF-like motifs, two mammalian homologues of Drosophila slitprotein, an unidentified LDL receptor-like protein, and three totallyuncharacterized proteins. The organization of the domains in theproteins, together with their expression profiles and fine chromosomallocations, has indicated their biological significance, demonstratingthat motif-trap screening is a powerful tool for the discovery of newgenes that have been difficult to identify by conventional methods.Genomics Jul. 1, 1998;51(1):27-34 PMID: 9693030, UI: 98360089

[0055] Flamingo, a seven-pass transmembrane cadherin, regulates planarcell polarity under the control of Frizzled. A seven-pass transmembranereceptor of the cadherin superfamily, designated Flamingo (Fmi),localized to cell-cell boundaries in the Drosophila wing. In the absenceof Fmi, planar polarity was distorted. Before morphological polarizationof wing cells along the proximal-distal (P-D) axis, Fmi wasredistributed predominantly to proximal and distal cell edges. Thisbiased localization of Fmi appears to be driven by an imbalance of theactivity of Frizzled (Fz) across the proximal/distal cell boundary.These results, together with phenotypes caused by ectopic expression offz and fini, suggest that cells acquire the P-D polarity by way of theFz-dependent boundary localization of Fmi. Cell Sep. 3,1999;98(5):585-95 PMID: 10490098, UI: 99418630

[0056] The various functions of MEGF, Flamingo and cadherin familymembers include, but are not limited to cell to cell adhesion, cell tomatrix adhesion, receptor-ligand interactions, immunological functions,vaso-permeability, cell recognition, tissue morphogenesis, cellproliferation, invasion and metastasis of malignant tumors.

[0057] Cell-cell and cell-matrix interactions that involve adhesionmolecules like cadherins are important in many developmental processes.Cadherins mediate homophilic, calcium-dependent cell-cell adhesion in awide variety of tissues and are important regulators of morphogenesis,and loss of function may be involved in the invasion and metastasis ofmalignant tumors. (OMIM ID600976)

[0058] NOV3

[0059] A disclosed NOV3 nucleic acid (SEQ ID NO:5) of 1438 nucleotides(also referred to as CG55806-01) encoding a novel Coagulation Factor1×Precursor-like protein is shown in Table 3A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 2-4 andending with a TAA codon at nucleotides 1184-1186. Putative untranslatedregions are found upstream from the initiation codon and downstream fromthe termination codon, and are underlined. The start and stop codons areshown in bold letters in Table 3A. TABLE 3A NOV3 nucleotide sequence. TATGCAGCGCGTGAACATGATCATGGCAGAATCACCAGGCCTCATCACCATCTGCCTTTTAGGA (SEQ IDNO:5) TATCTACTCAGTGCTGAATGTACAGTTTTTCTTGATCATGAAAACGCCAACAAAATTCTGAATCGGCCAAAGAGGTATAATTCAGGTAAATTGGAAGAGTTTGTTCAAGGGAACCTTGAGAGAGAATGTCTGGAGGAAAAGTGTAGTTTTGAAGAAGCACGAGAAGTTTTTGAAAACACTGAAAGAACAACTGAATTTTGGAAGCAGTATGTTGATGGAGATCAGTGTGAGTCCAATCCATGTTTAAATGGCGGCAGTTGCAAGGATGACATTAATTCCTATGAATGTTGGTGTCCCTTTGGATTTGAAGGAAAGAACTGTGAATTAGATGTGGACTATGTAAATTCTACTGAAGCTGAAACCATTTTGGATAACATCACTCAAAGCACCCAATCATTTAATGACTTCACTCGGGTTGTTGGTGGAGAAGATGCCAAACCAGGTCAATTCCCTTGGCAGGTTGTTTTGAATGGTAAAGTTGATGCATTCTGTGGAGGCTCTATCGTTAATGAAAAATGGATTGTAACTGCTGCCCACTGTGTTGAAACTGGTGTTAAAATTACAGTTGTCGCAGGTGAACATAATATTGAGGAGACAGAACATACAGAGCAAAAGCGAAATGTGATTCGAATTATTCCTCACCACAACTACAATGCAGCTATTAATAAGTACAACCATGACATTGCCCTTCTGGAACTGGACGAACCCTTAGTGCTAAACAGCTACGTTACACCTATTTGCATTGCTGACAAGGAATACACGAACATCTTCCTCAAATTTGGATCTGGCTATGTAAGTGGCTGGGGAAGAGTCTTCCACAAAGGGAGATCAGCTTTAGTTCTTCAGTACCTTAGAGTTCCACTTGTTGACCGAGCCACATGTCTTCGATCTACAAAGTTCACCATCTATAACAACATGTTCTGTGCTGGCTTCCATGAAGGAGGTAGAGATTCATGTCAAGGAGATAGTGGGGGACCCCATGTTACTGAAGTGGAAGGGACCAGTTTCTTAACTGGAATTATTAGCTGGGGTGAAGAGTGTGCAATGAAAGGCAAATATGGAATATATACCAAGGTATCCCGGTATGTCAACTGGATTAAGGAAAAAACAAAGCTCACTTAA TGAAAGATGGATTTCCAAGGTTAATTCATTGGAATTGAAAATTAACAGGGCCTCTCACTAACTAATCACTTTCCCATCTTTTGTTAGATTTGAATATATACATTCTATGATCATTGCTTTTTCTCTTTACAGGGGAGAATTTCATATTTTACCTGAGCAAATTGATTAGAAAATGGAACCACTAGAGGAATATAATGTGTTAGGAAATTACAGTCATTTCTAAGGGCCCAGCCTTGACAAATTGTGAGTAAA

[0060] The NOV3 disclosed in this invention maps to chromosome X.

[0061] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 1047 of 1047 bases(100%) identical to a gb:GENBANK-ID:A13997|acc:A13997.1 mRNA from Homosapiens (H. sapiens mRNA for factor IX).

[0062] A disclosed NOV3 polypeptide (SEQ ID NO:6) encoded by SEQ ID NO:5has 394 amino acid residues and is presented in Table 3B using theone-letter amino acid code. SignalP, Psort and/or Hydropathy resultspredict that NOV3 The results predict that this sequence is likely to belocalized extracellularly with a certainty of 0.5947. In an alternativeembodiment, NOV3 is likely to be localized to the lysosome (lumen) witha certainty of 0.1900, or to the endoplasmic reticulum (membrane) with acertainty of 0.1000, or to the endoplasmic reticulum (lumen) with acertainty 0.1000. The most likely cleavage site for a NOV3 peptide isbetween amino acids 25 and 26, ie., at the dash between amino acidsLLS-AE. TABLE 3B Encoded NOV3 protein sequence.MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNLEREC (SEQ IDNO:6) LEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNCELDVDYVNSTEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFHEGGRDSCQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT

[0063] The full amino acid sequence of the protein of the invention wasfound to have 264 of 264 amino acid residues (100%) identical to, and264 of 264 amino acid residues (100%) similar to, the 461 amino acidresidue ptnr:SWISSPROT-ACC:P00740 protein from Homo sapiens (Human)(COAGULATION FACTOR IX PRECURSOR (EC 3.4.21.22) (CHRISTMAS FACTOR)).

[0064] In a further search of public sequence databases, NOV3 was foundto have homology to the amino acid sequences shown in the BLASTP datalisted in Table 3C. TABLE 3C BLASTP results for NOV3 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expect ptnr:SWISSPROT- Coagulation factor IX 461 264/264 264/264 2.0e−219 ACC:P00740 precursor (EC 3.4.21.22) (100%) (100%) (Christmas factor) - Homosapiens ptnr: REMTREMBL- FACTOR IX - Homo sapiens 461 264/264 264/2642.0e−219 ACC: CAA00205 (100%) (100%) ptnr: SPTREMBL- COAGULATION FACTORXI - 461 263/264 264/264 4.2e−219 ACC: Q95ND7 Pan troglodytes (99%)(100%) ptnr: SPTREMBL- F9 (COAGULATION FACTOR 456 264/264 264/2648.9e−217 ACC: Q14316 IX (PLASMA (100%) (100%) THROMBOPLASTIC COMPONENT,CHRISTMAS DISEASE, HAEMOPHILIA B)) (FACTOR IX) - Homo sapiens ptnr:REMTREMBL- FACTOR IX PROTEIN - Homo 456 262/264 262/264 1.7e−215 ACC:CAA01607 sapiens (99%) (99%)

[0065] The homology of these sequences is shown graphically in theClustalW analysis shown in Table 3D. The NOV3 polypeptide is provided inlane 1.

[0066] BLAST analysis was performed on sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 3E. TABLE 3E Patp BLASTP Analysis for NOV3 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp: AAP50311 Sequence of human 461 264/264264/264 1.6e−219 factor IX, encoded by (100%) (100%) DNA FIX - Homosapiens patp: AAP50302 Sequence of human 461 264/264 264/264 1.6e−219factor IX - Homo (100%) (100%) sapiens patp: AAY97295 Human clottingfactor 461 264/264 264/264 1.6e−219 IX - Homo sapiens (100%) (100%)patp: AAB60281 Human factor IX (hFIX) 461 264/264 264/264 1.6e−219protein - Homo sapiens (100%) (100%) patp: AAP50019 Sequence of human461 263/264 263/264 1.1e−218 factor IX - Homo (99%) (99%) sapiens

[0067] Table 3F lists the domain description from DOMAIN analysisresults against NOV3. TABLE 3F Domain Analysis of NOV3 PSSMs producingsignificant alignments: Score (bits) Evalue gla 77.4 2.9e−19 EGF 32.78.5e−06 EB −14.5 5.4 trypsin 313.9 7.1e−99 Alignments of top-scoringdomains: gla: domain 1 of 1, from 52 to 93: score 77.4, E = 2.9e-19leelrkgnlerEcleEvCeleeArEifedtegtqefwrkYyd<-* (SEQ ID NO:97)|||+++||||||||||+|++|||||+||+||+|+|||++|+| NOV3 52LEEFVQGNLERECLEEKCSFEEAREVFENTERTTEFWKQYVD 93 EGF: domain 1 of 1, from97 to 128: score 32.7, E = 8.5e-06CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<- (SEQ ID NO:98)| +| ||+||| | +  +       +|+| || |     + ||+| NOV3 97CESN-PCLNGGSCKDDIN-------SYECWCPFG-----FEGKNC 128 EB: domain 1 of 1,from 79 to 128: score −14.5, E = 5.4CpsgqVevnGeCvkkvaiGetGClaseQCpgrwpGSqCidgm....C (SEQ ID NO:99)     +| + | +|+   |++ |+++  |++   |  | | +++ +| NOV3 79---ENTERTTEFWKQYVDGDQ-CESNP-CLN---GGSCKDDInsyeC 117 qCpeGftavnGvC<-* || ||   + +| 118 WCPFGF--EGKNC 128 trypsin: domain 1 of 1, from 160 to387: score 313.9, E = 7.1e-99IvGGreaqpgsfgsPwqvslqvrsgggsrkhfCGGsLisenwVLTAA (SEQ ID NO:100)+|||++|+||+|  |||| |+ +        |||||+++|+|++||| NOV3 160VVGGEDAKPGQF--PWQVVLNGKV-----DAFCGGSIVNEKWIVTAA 199HCvsgaasapassvrVSlsvrlGehnlsltegteqkfdvkktiivHpnyn|||+   + +   ++|    ++||||+++|| ++++||+ + ||+| ||| 200HCVET--GVK---ITV----VAGEHNIEETEHTEQKRNVIR-IIPHHNYN 239pdtldngaYdnDiALlkLkspgvtlgdtvrpicLps...assdlpvGttc+       | +|||||+|++| + |+++| |||+++++ ++  |+ | ++ 240AAINK---YNHDIALLELDEP-LVLNSYVTPICIADkeyTNIFLKFG-SG 284tvsGwGrrptknlg.lsdtLqevvvpvvsretCrsayeyggtdDkvefvt+||||||  +++ |+++ +||++ ||+|+|+|| ++  ++ |      ++ 285YVSGWGR--VFHKGrSALVLQYLRVPLVDRATCLRS--TKFT------IY 324dnmiCagal.ggkdaCqGDSGGPLvcsdgnrdgrwelvGivSwGsygCar+||+|||+ +||+|+||||||||+|++     |+ +|+||+||| + || 325NNMFCAGFHeGGRDSCQGDSGGPHVTEVE---GTSFLTGIISWG-EECAM 370gnkPGvytrVssyIdWI<-* ++|+|+||+||+|++|| 371 KGKYGIYTKVSRYVNWI 387

[0068] The Coagulation Factor 1×Precursor disclosed in this invention isexpressed in at least the following tissues: Adrenal Gland/Suprarenalgland, Artery, Bone, Brain, Colon, Lung, Mammary gland/Breast, PituitaryGland, Placenta, Spleen, Substantia Nigra, Testis, Thalamus, Thyroid,Uterus, and Whole Organism.

[0069] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from: Hemophilia B and otherdiseases, disorders and conditions of the like. Additional diseaseindications and tissue expression for NOV3 and NOV3 variants, ifavailable, are presented in the Examples.

[0070] Hemophilia B or Christmas disease is an X-linked condition causedby absent or reduced levels of functional coagulation factor IX. Basedupon the peptide sequence of bovine factor IX, Jagadeeswaran et al.(Somat Cell Mol Genet 1984;10:465-73) synthesized a 17-base pairoligonucleotide probe to screen a human liver cDNA library. Arecombinant clone was identified with a 917-nucleotide insert whosesequence corresponds to 70% of the coding region of human factor IX.This factor IX cDNA was used to probe restriction endonuclease digestedhuman DNA to identify a Taq I polymorphism associated with the genomicfactor 1×gene as well as to verify that there is a single copy of thisgene per haploid genome. The factor IX cDNA was also used to map thelocus for factor IX to a region from Xq26 to Xqter. The cloning of humanfactor IX cDNA and identification of a Taq I polymorphism and itsregional localization will provide a means to study the moleculargenetics of hemophilia B and permit linkage analysis with nearby loci.

[0071] NOV4

[0072] The NOV4 (alternatively referred to as CG55936-01) nucleic acidof 1108 nucleotides (SEQ ID NO:7) encodes a novel carbonic anhydrase IVprecursor-like protein and is shown in Table 4A. An open reading framefor the mature protein was identified beginning with a ATG initiationcodon at nucleotides 38-40 and ending with a TGA codon at nucleotides1046-1048. Putative untranslated regions upstream from the start codonand downstream from the termination codon are underlined in Table 4A.The start and stop codons are in bold letters. TABLE 4A NOV4 NucleotideSequence (SEQ ID NO:7) CGACCCCGGCTCAGAGGACTCTTTGCTGTCCCGCAAGATGCGGATGCTGCTGGCGCTCCTGGCCCTCTCCGCGGCGCGGCCATCGGCCAGTGCAGAGTCACACTGGTGCTACGAGGTTCAAGCCGAGTCCTCCAACTACCCCTGCTTGGTGCCAGTCAAGTGGGGTGGAAACTGCCAGAAGGACCGCCAGTCCCCCATCAACATCGTCACCACCAAGGCAAAGGTGGACAAAAAACTGGGACGCTTCTTCTTCTCTGGCTACGATAAGAAGCAAACGTGGACTGTCCAAAATAACGGGCACTCAGTGATGATGTTGCTGGAGAACAAGGCCAGCATTTCTGGAGGAGGACTGCCTGCCCCATACCAGGCCAAACAGTTGCACCTGCACTGGTCCGACTTGCCATATAAGGGCTCGGAGCACAGCCTCGATGGGGAGCACTTTGCCATGGAGATGCACATAGTACATGAGAAAGAGAAGGGGACATCGAGGAATGTGAAAGAGGCCCAGGACCCTGAAGACGAAATTGCGGTGCTGGCCTTTCTGGTGGAGATCGGGAGAATGAACTGGCCACCACCACTGGCTCCCTGCAGACTTTCTCAAGACCCTTCCCTCCCTTTCCAGGCTGGAACCCAGGTGAACGAGGGCTTCCAGCCACTGGTGGAGGCACTGTCTAATATCCCCAAACCTGAGATGAGCACTACGATGGCAGAGAGCAGCCTGTTGGACCTGCTCCCCAAGGAGGAGAAACTGAGGCACTACTTCCGCTACCTGGGCTCACTCACCACACCGACCTGCGATGAGAAGGTCGTCTGGACTGTGTTCCGGGAGCCCATTCAGCTTCACAGAGAACAGATCCTGGCATTCTCTCAGAAGCTGTACTACGACAAGGAACAGACAGTGAGCATGAAGGACAATGTCAGGCCCCTGCAGCAGCTGGGGCAGCGCACGGTGATAAAGTCCGGGGCCCCGGGTCGGCCGCTGCCCTGGGCCCTGCCTGCCCTGCTGGGCCCCATGCTGGCCTGCCTGCTGGCCGGCTTCCTGCGATGATGGCTCACTTCTGCAC GCAGCCTCTCTGTTGCCTCAGCTCTCCAAGTTCCAGGCTTCCGG

[0073] The NOV4 of the invention maps to chromosomes 17.

[0074] In a search of sequence databases, it was found, for example,that the NOV4 nucleic acid sequence of this invention has 586 of 608bases (96%) identical to a gb:GENBANK-ID:HUMCAIVA|acc:M83670.1 mRNA fromHomo sapiens (Human carbonic anhydrase IV mRNA, complete cds).

[0075] The NOV4 polypeptide (SEQ ID NO:8) encoded by SEQ ID NO:7 is 336amino acid residues in length and is presented using the one-letteramino acid code in Table 4B. The SignalP, Psort and/or Hydropathyresults predict that NOV4 has a signal peptide and is likely to belocalized in the plasma membrane with a certainty of 0.9190. Inalternative embodiments, a NOV4 polypeptide is located to the lysosomemembrane with a certainty of 0.2000, the endoplasmic reticulum membranewith a certainty of 0.1000, or the endoplasmic reticulum lumen with acertainty of 0.1000. The SignalP predicts a likely cleavage site for aNOV4 peptide is between amino acid positions 19 and 20, i.e. at the dashin the sequence ASA-ES. TABLE 4B Encoded NOV4 Protein Sequence (SEQ IDNO:8)MRMLLALLALSAARPSASAESHWCYEVQAESSNYPCLVPVKWGGNCQKDRQSPINIVTTKAKVDKKLGRFFFSGYDKKQTWTVQNNGHSVMMLLENKASISGGGLPAPYQAKQLHLHWSDLPYKGSEHSLDGEHFAMEMHIVHEKEKGTSRNVKEAQDPEDEIAVLAFLVEIGRMNWPPPLAPCRLSQDPSLPFQAGTQVNEGFQPLVEALSNIPKPEMSTTMAESSLLDLLPKEEKLRHYFRYLGSLTTPTCDEKVVWTVFREPIQLHREQILAFSQKLYYDKEQTVSMKDNVRPLQQLGQRTVIKSGAPGRPLPWALPALLGPMLACLLAGFLR

[0076] The fill amino acid sequence of the disclosed protein of theinvention has 172 of 173 amino acid residues (99%) identical to, and 172of 173 amino acid residues (99%) similar to, the 312 amino acid residueptnr:SWISSNEW-ACC:P22748 protein from Homo sapiens (Human) (CARBONICANHYDRASE IV PRECURSOR (EC 4.2.1.1) (CARBONATE DEHYDRATASE IV) (CA-IV)).

[0077] The amino acid sequence of NOV4 has high homology to otherproteins as shown in Table 4C. TABLE 4C NOV4 BLASTP Results Length GeneIndex/ of Identity Expect Identifier Protein/Organism aa (%) Positives(%) Value P22748 Carbonic 312 172/173 172/173 7.2e−167 anhydrase IVprecursor (99%) (99%) (EC 4.2.1.1) (Carbonate dehydratase IV) (CA-IV) -Homo sapiens Q95323 Carbonic anhydrase IV 312 125/203 144/203 3.4e−113precursor (EC 4.2.1.1) (61%) (70%) (Carbonate dehydratase IV) (CA-IV) -Bos taurus (Bovine) P48283 Carbonic anhydrase IV 308 119/176 135/1764.5e−107 precursor (EC 4.2.1.1) (67%) (76%) (Carbonate dehydratase IV)(CA-IV) - Oryctolagus cuniculus (Rabbit) P48284 Carbonic anhydrase IV309  96/173 126/173 3.0e−93 precursor (EC 4.2.1.1) (55%) (72%)(Carbonate dehydratase IV) (CA-IV) - Rattus norvegicus (Rat) Q64444Carbonic anhydrase IV 305  94/173 120/173 1.3e−88 precursor (EC 4.2.1.1)(54%) (69%) (Carbonate dehydratase IV) (CA-IV) - Mus musculus (Mouse)

[0078] A multiple sequence alignment is given in Table 4D in a ClustalWanalysis comparing NOV4 with related protein sequences disclosed inTable 4C.

[0079] Additional BLAST results are shown in Table 4E. TABLE 4E PatpBLASTP Analysis for NOV4 Sequences producing High- scoring SegmentLength Identity Pairs Protein/Organism (aa) (%) Positive (%) E Valuepatp: AAB59591 Human carbonic 268 154/155 154/155 1.3e−143 anhydraseisoform (99%) (99%) patp: AAB54035 Human pancreatic 198 133/154 135/1543.8e−69 cancer antigen protein (86%) (87%) sequence patp: AAR91952 Lungcancer specific 270  50/126  73/126 2.8e−32 antigen HCAVIII (39%) (57%)truncated protein patp: AAR91953 Lung cancer specific 274  50/126 73/126 2.8e−32 antigen HCAVIII (39%) (57%) truncated protein patp:AAR91950 Lung cancer specific 354  59/174  90/174 1.1e−30 antigenHCAVIII pre- (33%) (51%) protein

[0080] Domain results for NOV4 were collected from the Pfam database,and then identified by the Interpro domain accession number. The resultsare listed in Table 4F with the statistics and domain description. Theseresults indicate that the NOV4 polypeptide has properties similar tothose of other proteins known to contain these domains. TABLE 4F DOMAINANALYSIS OF NOV4 Score E PSSMs Producing Significant Alignments (bits)Value carb_anhydrase: domain 1 of 2, from 23 to 176 294.4 1.4e−84WgYgehngpehsnnahvlWhklyPiAnGGnCqGerQSPInIqtkeak (SEQ ID NO:106)|+|++++++++       +++++|+++||+|++++||||+|++++++ NOV4WCYEVQAESSN-------YPCLVPVKWGGNCQKDRQSPINIVTTKAKyDPsLkpLslSYdaatakefeivNnGHsfqVeFdDsddksvlsGGPLpaG+|++|+++++|+++++++ ++++|+||++++ +++   +++++||+|++ NOV4VDKKLGRFFFSGYDKKQT-WTVQNNGHSVMMLLEN---KASISGGGLPA-hpYRLkQfHFHWGGAssddqGSEHTVDGkkYaaELHLVHWNs.tKYgsyk +|+++|+|+||+  +++++||||++||+++++|+|+||+++++++++++ NOV4-PYQAKQLHLHWS--DLPYKGSEHSLDGEHFAMEMHIVHEKEkGTSRNVKeAvskpDGLAVlGvFlkvGdyqen +|++++|++||+++++++|  + +EAQDPEDEIAVLAFLVEIG--RMN carb_anhydrase: domain 2 of 2, from 195 to 309207.5 2.1e−58 kvGdyqenpglqkvvDaLssIktKGksatftnFDPStLLPse.klrD (SEQ IDNO:107) ++| +++++++++++++|++|++++++++++++++ +|||+++++++ NOV4QAG-TQVNEGFQPLVEALSNIPKPEMSTTMAESSLLDLLPKEeKLRHYWTYpGSLTTPPLtEsVtWiVlkepIsvSseQllkFRsLlfnaegeeevp|++|+||||||+++|+|+|+|++++|+++++|+++|++++++++ +++++ NOV4YFRYLGSLTTPTCDEKVVWTVFREPIQLHREQILAFSQKLYYDK-EQTVSGCdGimvdNyRPtQPLkgRvVrASF      +++|+||+|+|++|+|++|+ NOV4-----MKDNVRPLQQLGQRTVIKSG

[0081] The carbonic anhydrase disclosed in this invention is expressedin at least the following tissues: bone, brain, colon, kidney, lung,pancreas, parathyroid gland, peripheral blood, prostate, substantianigra, and thalamus. This information was derived by determining thetissue sources of the sequences that were included in the inventionincluding but not limited to SeqCalling sources, Public EST sources,Literature sources, and/or RACE sources. The protein similarityinformation, expression pattern, and map location for the NOV4 proteinand nucleic acid disclosed herein suggest that this protein may haveimportant structural and/or physiological functions characteristic ofthe carbonic anhydrases family. Therefore, the NOV4 nucleic acids andproteins of the invention are useful in potential diagnostic andtherapeutic applications and as a research tool. For example, thecompositions of the present invention will have efficacy for treatmentof patients suffering from: renal abnormalities, CO2 andHCO3-homeostasis in brain and other diseases, disorders and conditionsof the like. The novel NOV4 nucleic acids and polypeptides of theinvention, or fragments thereof, are useful in diagnostic applications,wherein the presence or amount of the nucleic acid or the protein are tobe assessed. These materials are further useful in the generation ofantibodies that bind immunospecifically to the novel substances of theinvention for use in therapeutic or diagnostic methods. These antibodiesmay be generated according to methods known to one ordinarily skilled inthe art, using prediction from hydrophobicity charts, as described inthe “Anti-NOVX Antibodies” section below.

[0082] The disclosed NOV4 protein of the invention has multiplehydrophilic regions, each of which can be used as an immunogen. The NOV4protein also has value in the development of a powerful assay system forfunctional analysis of various human disorders, which will help inunderstanding of pathology of the disease and development of new drugtargets for various disorders.

[0083] Carbonic anhydrases form a large family of genes encoding zincmetalloenzymes of great physiologic importance. As catalysts of thereversible hydration of carbon dioxide, these enzymes participate in avariety of biologic processes, including respiration, calcification,acid-base balance, bone resorption, and the formation of aqueous humor,cerebrospinal fluid, saliva, and gastric acid. Thus, it is likely thatthe NOV4 protein of the invention is accessible to a diagnostic probeand for the various therapeutic applications described herein.

[0084] NOV5

[0085] The NOV5 nucleic acid of 1806 nucleotides (SEQ ID NO:9)(alternatively referred to as CG55784-01) encodes a novel neural celladhesion molecule-like protein and is shown in Table 5A. An open readingframe for the mature protein was identified beginning with an AACinitiation codon at nucleotides 1-3 and ending with a TAA codon atnucleotides 1645-1647. Putative untranslated regions downstream from thetermination codon are underlined in Table 5A. The start and stop codonsare in bold letters. TABLE 5A NOV5 Nucleotide Sequence (SEQ ID NO:9)AACAAAGCCATCCCCGGAGGAAAGGAGACGTCGGTCACCATTGACATCCAGCACCCTCCACTGGTCAACCTCTCGGTGGAGCCACAGCCAGTGCTGGAGGACAACGTCGTCACTTTCCACTGCTCTGCAAAGGCCAACCCAGCTGTCACCCAGTACAGGTGGGCCAAGCGGGGCCAGATCATCAAGGAGGCATCTGGAGAGGTGTACAGGACCACAGTGGACTACACGTACTTCTCAGAGCCCGTCTCCTGTGAGGTGACCAAAGCCCTGGGCAGCACCAACCTCAGCCGCACGGTTGACGTCTACTTTGGGCCCCGGATGACCACAGAACCCCAATCCTTGCTCGTGGATCTGGGCTCTGATGCCATCTTAAGCTGCGCCTGGACCGGCAACCCATCCCTGACCATCGTCTGGATGAAGCGGGGCTCCGGAGTGGTCCTGAGCAATGAGAAGACCCTGACCCTCAAATCCGTGCGCCAGGAGGACGCGGGCAAGTACGTGTGCCGGGCTGTGGTGCCCCGTGTGGGAGCCGGGGAGAGAGAGGTGACCCTGACCGTCAATGGACCCCCCATCATCTCCAGCACCCAGACCCAGCACGCCCTCCACGGCGAGAAGGGCCAGATCAAGTGCTTCATCCGGAGCACGCCGCCGCCGGACCGCATCGCCTGGTCCTGGAAGGAGAACGTTCTGGAGTCGGGCACATCGGGGCGCTATACGGTGGAGACCATCAGCACCGAGGAGGGCGTCATCTCCACCCTGACCATCAGCAACATCGTGCGGGCCGACTTCCAGACCATCTACAACTGCACGGCCTGGAACAGCTTCGGCTCCGACACTGAGATCATCCGGCTCAAGGAGCAAGGTTCGGAAATGAAGTCGGGAGCCGGGCTGGAAGCAGAGTCTGTGCCGATGGCCGTCATCATTGGGGTGGCCGTAGGAGCTGGTGTGGCCTTCCTCGTCCTTATGGCAACCATCGTGGCGTTCTGCTGTGCCCGTTCCCAGAGAAATCTCAAAGGTGTTGTGTCAGCCAAAAATGATATCCGAGTGGAAATTGTCCACAAGGAACCAGCCTCTGGTCGGGAGGGTGAGGAGCACTCCACCATCAAGCAGCTGATGATGGACCGGGGTGAATTCCAGCAAGACTCAGTCCTGAAACAGCTGGAGGTCCTCAAAGAAGAGGAGAAAGAGTTTCAGAACCTGAAGGACCCCACCAATGGCTACTACAGCGTCAACACCTTCAAAGAGCACCACTCAACCCCGACCATCTCCCTCTCCAGCTGCCAGCCCGACCTGCGTCCTGCGGGCAAGCAGCGTGTGCCCACAGGCATGTCCTTCACCAACATCTACAGCACCCTGAGCGGCCAGGGCCGCCTCTACGACTACGGGCAGCGGTTTGTGCTGGGCATGGGCAGCTCGTCCATCGAGCTTTGTGAGCGGGAGTTCCAGAGAGGCTCCCTCAGCGACAGCAGCTCCTTCCTGGACACGCAGTGTGACAGCAGCGTCAGCAGCAGCGGCAAGCAGGATGGCTATGTGCAGTTCGACAAGGCCAGCAAGGCTTCTGCTTCCTCCTCCCACCACTCCCAGTCCTCGTCCCAGAACTCTGACCCCAGTCGACCCCTGCAGCGGCGGATGCAGACTCACGTCTAAGGATCACACACCGCGGGTGGGGACGGGCCAGGGAAGAGGTCAGGGCACGTTCTGGTTGTCCAGGGACTGTGGGGTACTTTACAGAGGACACCAGAATGGCCCACTTCCAGGACAGCCTCCCAGCGCCTCTGCCACTGCCTTCCTTCGAAGCTCTGATCA

[0086] The NOV5 of the invention maps to chromosome 11.

[0087] In a search of sequence databases, it was found, for example,that the NOV5 nucleic acid sequence of this invention has 564 of 919bases (61%) identical to a gb:GENBANK-ID:AK022708|acc:AK022708.1 mRNAfrom Homo sapiens (Homo sapiens cDNA FLJ12646 fis, clone NT2RM4001987,weakly similar to NEURAL CELL ADHESION MOLECULE 1, LARGE ISOFORMPRECURSOR).

[0088] The NOV5 polypeptide (SEQ ID NO:10) encoded by SEQ ID NO:9 is 548amino acid residues in length and is presented using the one-letteramino acid code in Table 5B. The SignalP, Psort and/or Hydropathyresults predict that NOV5 has no known signal peptide and is likely tobe localized in the plasma membrane with a certainty of 0.7000. Inalternative embodiments, a NOV5 polypeptide is located to theendoplasmic reticulum membrane with a certainty of 0.2000, or themitochondrial inner membrane with a certainty of 0.1000. TABLE 5BEncoded NOV5 Protein Sequence (SEQ ID NO:10)NKAIPGGKETSVTIDIQHPPLVNLSVEPQPVLEDNVVTFHCSAKANPAVTQYRWAKRGQIIKEASGEVYRTTVDYTYFSEPVSCEVTKALGSTNLSRTVDVYFGPRMTTEPQSLLVDLGSDAILSCAWTGNPSLTIVWMKRGSGVVLSNEKTLTLKSVRQEDAGKYVCRAVVPRVGAGEREVTLTVNGPPIISSTQTQHALHGEKGQIKCFIRSTPPPDRIAWSWKENVLESGTSGRYTVETISTEEGVISTLTISNIVRADFQTIYNCTAWNSFGSDTEIIRLKEQGSEMKSGAGLEAESVPMAVIIGVAVGAGVAFLVLMATIVAFCCARSQRNLKGVVSAKNDIRVEIVHKEPASGREGEEHSTIKQLMMDRGEFQQDSVLKQLEVLKEEEKEFQNLKDPTNGYYSVNTFKEHHSTPTISLSSCQPDLRPAGKQRVPTGMSFTNIYSTLSGQGRLYDYGQRFVLGMGSSSIELCEREFQRGSLSDSSSFLDTQCDSSVSSSGKQDGYVQFDKASKASASSSHHSQSSSQNSDPSRPLQRRMQTHV

[0089] The full amino acid sequence of the disclosed protein of theinvention has 244 of 570 amino acid residues (42%) identical to, and 334of 570 amino acid residues (58%) similar to, the 571 amino acid residueptnr:TREMBLNEW-ACC:BAB14192 protein from Homo sapiens (Human) (cDNAFLJ12646 FIS, CLONE NT2RM4001987, WEAKLY SIMILAR TO NEURAL CELL ADHESIONMOLECULE 1, LARGE ISOFORM PRECURSOR).

[0090] The amino acid sequence of NOV5 has high homology to otherproteins as shown in Table 5C. TABLE 5C NOV5 BLASTP Results Length GeneIndex/ of Identity Expect Identifier Protein/Organism aa (%) Positives(%) Value Q96JG0 KIAA1867 PROTEIN - 779 546/548 546/548 1.6e−292 Homosapiens (Human) (99%) (99%) Q9H9N1 NT2RM4001987 PROTEIN - 571 244/570334/570 5.3e−104 Homo sapiens (Human) (42%) (58%) Q96J84 NEPH1 - Homosapiens 605 198/386 256/386 9.2e−100 (Human) (51%) (66%) Q9NVA5NT2RP4001372 PROTEIN - 410 169/410 236/410 4.2e−63 Homo sapiens (Human)(41%) (57%) Q923L4 NEPH1 - Mus musculus 392  90/166 113/166 2.4e−46(Mouse) (54%) (68%)

[0091] A multiple sequence alignment is given in Table 5D in a ClustalWanalysis comparing NOV5 with related protein sequences disclosed inTable 5C.

[0092] Additional BLAST results are shown in Table 5E. TABLE 5E PatpBLASTP Analysis for NOV5 Sequences producing High- scoring SegmentLength Identity Pairs Protein/Organism (aa) (%) Positive (%) E Valuepatp: AAU12278 Human PRO4502 245 245/245 245/245 8.6e−127 polypeptidesequence (100%) (100%) patp: AAB37996 Human secreted protein 257 238/258238/258 5.4e−118 encoded by gene 13 (92%) (92%) clone HIBEU15 patp:AAE07070 Human gene 20 encoded 712 244/570  73/126 4.1e−104 secretedprotein (42%) (57%) HDTJG33 patp: AAB94206 Human protein sequence 571244/570 334/570 4.1e−104 (42%) (58%) patp: AAU17986 Human immunoglobulin550 187/371 242/371 2.3e−94 polypeptide (50%) (65%)

[0093] Domain results for NOV5 were collected from the Pfarn database,and then identified by the Interpro domain accession number. The resultsare listed in Table 5F with the statistics and domain description. Theseresults indicate that the NOV5 polypeptide has properties similar tothose of other proteins known to contain these domains. TABLE 5F DOMAINANALYSIS OF NOV5 Score PSSMs Producing Significant Alignments (bits) EValue Immunoglobulin (Ig): domain 2 of 3, from 119 to 170 33.6 7.5e−09GesvtLtCsvsgfgpp.p.vtWlrngk.......lslti.svtpeDs (SEQ ID NO:113)|+++ |+|  +  ++++ ++ | + + +   +++ ++++++++++|+ NOV5GSDAILSCAWT--GNPsLtIVWMKRGSgvvlsneKTLTLkSVRQEDA gGtYtCvv  | | |++-GKYVCRA

[0094] The neural cell adhesion molecule disclosed in this invention isexpressed in at least the following tissues: amygdala, brain, placenta,spinal chord. In addition, the sequence is predicted to be expressed inthe following tissues because of the expression pattern of (GENBANK-ID:gb:GENBANK-ID:AK022708|acc:AK022708.1) a closely related Homo sapienscDNA FLJ12646 fis, clone NT2RM4001987, weakly similar to NEURAL CELLADHESION MOLECULE 1, LARGE ISOFORM PRECURSOR homolog in species Homosapiens: kidney.

[0095] The protein similarity information, expression pattern, and maplocation for the NOV5 protein and nucleic acid disclosed herein suggestthat this protein may have important structural and/or physiologicalfunctions characteristic of the cell adhesion molecule family.Therefore, the NOV5 nucleic acids and proteins of the invention areuseful in potential diagnostic and therapeutic applications and as aresearch tool. For example, the compositions of the present inventionwill have efficacy for treatment of patients suffering from: VonHippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis,ataxia-telangiectasia, leukodystrophies, behavioral disorders,addiction, anxiety, pain, neuroprotection, fertility, diabetes,autoimmune disease, renal artery stenosis, interstitial nephritis,glomerulonephritis, polycystic kidney disease, systemic lupuserythematosus, renal tubular acidosis, IgA nephropathy, hypercalceimia,and other diseases, disorders and conditions of the like.

[0096] The novel NOV5 nucleic acids and polypeptides of the invention,or fragments thereof, are useful in diagnostic applications, wherein thepresence or amount of the nucleic acid or the protein are to beassessed. These materials are further useful in the generation ofantibodies that bind immunospecifically to the novel substances of theinvention for use in therapeutic or diagnostic methods. These antibodiesmay be generated according to methods known to one ordinarily skilled inthe art, using prediction from hydrophobicity charts, as described inthe “Anti-NOVX Antibodies” section below.

[0097] The disclosed NOV5 protein of the invention has multiplehydrophilic regions, each of which can be used as an immunogen. The NOV5protein also has value in the development of a powerful assay system forfunctional analysis of various human disorders, which will help inunderstanding of pathology of the disease and development of new drugtargets for various disorders.

[0098] Neural cell adhesion molecules (NCAM) are members of the celladhesion molecule family with homology to the immunoglobulin proteinsuperfamily. They play critical roles in neuronal outgrowth,differentiation and development, as well as oligodendrocyte maturationand myelination, probably by modulating cell-cell interactions. NCAMscan also reorganize the extra-cellular space and cause disturbances thatdrive the development of brain pathology in conditions such asAlzheimer's disease and multiple sclerosis. Disease-causing mutationsand gene knock-out studies further substantiat that neural cell adhesionmolecules are required for axon guidance, brain plasticity, long termpotentiation, learning and neuron regeneration. Therefore, theseproteins are essential for brain function and may be used as therapeutictargets in that context.

[0099] NOV6

[0100] The NOV6 nucleic acid (SEQ ID NO:11) (alternatively referred toas CG55916-01) of 2405 nucleotides encodes a novel phospholipase Cdelta-like protein and is shown in Table 6A. An open reading frame forthe mature protein was identified beginning with a ATG initiation codonat nucleotides 153-155 and ending with a TGA codon at nucleotides2361-2363. Putative untranslated regions upstream from the start codonand downstream from the termination codon are underlined in Table 6A.The start and stop codons are in bold letters. TABLE 6A NOV6 NucleotideSequence (SEQ ID NO:11)GCGGCCGCTGGAGGCGTTGCCGCCGCCCGCCCGAGGAGCCCCCGGTGGCCGCCCAGGTCGCAGCCCAAGTCGCGGCGCCGGTCGCTCTCCCGTCCCCGCCGACTCCCTCCGATGGCGGCACCAAGAGGCCCGGGCTGCGGGCGCTGAAGAAG ATGGGCCTGACGGAGGACGAGGACGTGCGCGCCATGCTGCGGGGCTCCCGGCTCCGCAAGATCCGCTCGCGCACGTGGCACAAGGAGCGGCTGTACCGGCTGCAGGAGGACGGCCTGAGCGTGTGGTTCCAGCGGCGCATCCCGCGTGCGCCATCGCAGCACATCTTCTTCGTGCAGCACATCGAGGCGGTCCGCGAGGGCCACCAGTCCGAGGGCCTGCGGCGCTTCGGGGGTGCCTTCGCGCCAGCGCGCTGCCTCACCATCGCCTTCAAGGGCCGCCGCAAGAACCTGGACCTGGCGGCGCCCACGGCTGAGGAAGCGCAGCGCTGGGTGCGCGGTCTGACCAAGCTCCGCGCGCGCCTGGACGCCATGAGCCAGCGCGAGCGGCTAGACCAATGGATCCACTCCTATCTGCACCGGGCTGACTCCAACCAGGACAGCAAGATGAGCTTCAAGGAGATCAAGAGCCTGCTGAGAATGGTCAACGTGGACATGAACGACATGTACGCCTACCTCCTCTTCAAGGAGTGTGACCACTCCAACAACGACCGTCTAGAGGGGGCTGAGATCGAGGAGTTCCTGCGGCGGCTGCTGAAGCGGCCGGAGCTGGAGGAGATCTTCCATCAGTACTCGGGCGAGGACCGCGTGCTGAGTGCCCCTGAGCTGCTGGAGTTCCTGGAGGACCAGGGCGAGGAGGGCGCCACACTGGCCCGCGCCCAGCAGCTCATTCAGACCTATGAGCTCAACGAGACAGCCCCTGCAGCCAAGCAGCATGAGCTGATGACACTGGATGGCTTCATGATGTACCTGTTGTCGCCGGAGGGGGCTGCCTTGGACAACACCCACACGTGTGTGTTCCAGGACATGAACCAGCCCCTTGCCCACTACTTCATCTCTTCCTCCCACAACACCTATCTGACTGACTCCCAGATCGGGGGGCCCAGCAGCACCGAGGCCTATGTTAGGGCCTTTGCCCAGGGATGCCGCTGCGTGGAGCTGGACTGCTGGGAGGGGCCAGGAGGGGAGCCCGTCATCTATCATGGCCATACCCTCACCTCCAAGATTCTCTTCCGGGACGTGGTCCAAGCCGTGCGCGACCATGCCTTCACGGTGAGCCCTTACCCTGTCATCCTATCCCTGGAGAACCACTGCGGGCTGGAGCAGCAGGCTGCCATGGCCCGCCACCTCTGCACCATCCTGGGGGACATGCTGGTGACACAGGCGCTGGACTCCCCAAATCCCGAGGAGCTGCCATCCCCAGAGCAGCTGAAGGGCCGGGTCCTGGTGAAGGGAAAGAAGTTGCCCGCTGCTCGGAGCGAGGATGGCCGGGCTCTGTCGGATCGGGAGGAGGAGGAGGAGGATGACGAGGAGGAAGAAGAGGAGGTGGAGGCTGCAGCGCAGAGGCAGATCTCCCCGGAGCTGTCGGCCCTGGCTGTGTACTGCCACGCCACCCGCCTGCGACCCGACACATCACCTGGAGGACTAGGAAGCAGCCAGGTGAAGAGGGGAGAGCGCTTTCCAGACAGGAGGAACAGGTTGTTGAAGGCCTGGGGGAACAGCTTTGTCAGGCACAATGCCCGCCAGCTGACCCGCGTGTACCCGCTGGGGCTGCGGATGAACTCAGCCAACTACAGTCCCCAGGAGATGTGGAACTCGGGCTGTCAGCTGGTGGCCTTGAACTTCCAGACGCCAGGCTACGAGATGGACCTCAATGCCGGGCGCTTCCTAGTCAATGGGCAGTGTGGCTACGTCCTAAAACCTGCCTGCCTGCGGCAACCTGACTCGACCTTTGACCCCGAGTACCCAGGACCTCCCAGAACCACTCTCAGCATCCAGGTGCTGACTGCACAGCAGCTGCCCAAGCTGAATGCCGAGAAGCCACACTCCATTGTGGACCCCCTGGTGCGCATTGAGATCCATGGGGTGCCCGCAGACTGTGCCCGGCAGGAGACTGACTACGTGCTCAACAATGGCTTCAACCCCCGCTGGGGGCAGACCCTGCAGTTCCAGCTGCGGGCTCCGGAGCTGGCACTGGTCCGGTTTGTGGTGGAAGATTATGACGCCACCTCCCCCAATGACTTTGTGGGCCAGTTTACACTGCCTCTTAGCAGCCTAAAGCAAGGGTACCGCCACATACACCTGCTTTCCAAGGACGGGGCCTCACTGTCACCAGCCACGCTCTTCATCCAAATCCGCATCCAGCGCTCCTGA GGGCCCACCTCACTCGCCTTGGGGTTCTGCGAGTGCCAGTCC

[0101] The NOV6 of the invention maps to chromosomes 17.

[0102] In a search of sequence databases, it was found, for example,that the NOV6 nucleic acid sequence of this invention has 956 of 1425bases (67%) identical to a acc:U09117.1 mRNA from human (Humanphospholipase C delta 1 mRNA, complete cds—Homo sapiens, 2627 bp).

[0103] The NOV6 polypeptide (SEQ ID NO: 12) encoded by SEQ ID NO:11 is736 amino acid residues in length and is presented using the one-letteramino acid code in Table 6B. The SignalP, Psort and/or Hydropathyresults predict that NOV6 has no known signal peptide and is likely tobe localized in the mitochondrial matrix space with a certainty of0.3600. In alternative embodiments, a NOV6 polypeptide is located to themicrobody (peroxisome) with a certainty of 0.3000, or the lysosome(lumen) with a certainty of 0.1626. TABLE 6B Encoded NOV6 ProteinSequence (SEQ ID NO:12)MGLTEDEDVRAMLRGSRLRKIRSRTWHKERLYRLQEDGLSVWFQRRIPRAPSQHIFFVQHIEAVREGHQSEGLRRFGGAFAPARCLTIAFKGRRKNLDLAAPTAEEAQRWVRGLTKLRARLDAMSQRERLDQWIHSYLHRADSNQDSKMSFKEIKSLLRMVNVDMNDMYAYLLFKECDHSNNDRLEGAEIEEFLRRLLKRPELEEIFHQYSGEDRVLSAPELLEFLEDQGEEGATLARAQQLIQTYELNETAPAAKQHELMTLDGFMMYLLSPEGAALDNTHTCVFQDMNQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVVQAVRDHAFTVSPYPVILSLENHCGLEQQAAMARHLCTILGDMLVTQALDSPNPEELPSPEQLKGRVLVKGKKLPAARSEDGRALSDREEEEEDDEEEEEEVEAAAQRQISPELSALAVYCHATRLRPDTSPGGLGSSQVKRGERFPDRRNRLLKAWGNSFVRHNARQLTRVYPLGLRMNSANYSPQEMWNSGCQLVALNFQTPGYEMDLNAGRFLVNGQCGYVLKPACLRQPDSTFDPEYPGPPRTTLSIQVLTAQQLPKLNAEKPHSIVDPLVRIEIHGVPADCARQETDYVLNNGFNPRWGQTLQFQLRAPELALVRFVVEDYDATSPNDFVGQFTLPLSSLKQGYRHIHLLSKDGASLSPATLFIQIRIQRS

[0104] The full amino acid sequence of the disclosed protein of theinvention has 388 of 744 amino acid residues (52%) identical to, and 511of 744 amino acid residues (68%) similar to, the 756 amino acid residueptnr:SPTREMBL-ACC:Q9Z1B4 from mouse (PHOSPHOLIPASE C-DELTA1).

[0105] The amino acid sequence of NOV6 has high homology to otherproteins as shown in Table 6C. TABLE 6C NOV6 BLASTP Results Length GeneIndex/ of Identity Expect Identifier Protein/Organism aa (%) Positives(%) Value CAC88658 SEQUENCE 1 FROM 736 707/736 713/736 0.0 PATENTWO0166764 - Homo (96%) (96%) sapiens (Human) Q96FL6 SIMILAR TO 2998584/613 590/613 3.1e−312 PHOSPHOLIPASE C, DELTA - (95%) (96%) Homosapiens (Human) Q60450 PHOSPHOLIPASE C-DELTA1 - 1975 384/744 520/7448.0e−204 Cricetulus griseus (51%) (69%) (Chinese hamster) Q9Z1B4PHOSPHOLIPASE C DELTA-1 - 1941 388/744 511/744 3.2e−200 Mus musculus(Mouse) (52%) (68%) P51178 1-phosphatidylinositol - 1937 381/744 509/7448.5e−200 4,5-bisphosphate (51%) (68%) phosphodiesterase delta 1 (EC3.1.4.11) (PLC- delta-1) (Phospholipase C-delta-1) (PLC-III) - Homosapiens (Human)

[0106] A multiple sequence alignment is given in Table 6D in a ClustalWanalysis comparing NOV6 with related protein sequences disclosed inTable 6C.

[0107] Additional BLASTP results are shown in Table 6E. TABLE 6E PatpBLASTP Analysis for NOV6 Sequences producing High- scoring SegmentLength Identity Positive Pairs Protein/Organism (aa) (%) (%) E Valuepatp:AAG63220 Amino acid sequence of 789 707/736 713/736 0.0 a humanlipid (96%) (96%) metabolism enzyme patp:AAB47516 Human phospholipase C,736 707/736 713/736 0.0 16835 (96%) (96%) patp:AAY81394 Ratphospholipase C- 756 382/744 509/744 2.2e-199 delta-1 (51%) (68%)patp:AAW01596 Inositol-1,4,5- 1096 260/733 380/733 1.1e-105 triphosphatebinding (35%) (51%) protein patp:AAR90583 Phospholipase C- 1290 149/392220/392 3.3e-105 gamma-1 (38%) (56%)

[0108] Domain results for NOV6 were collected from the Pfam database,and then identified by the Interpro domain accession number. The resultsare listed in Table 6F with the statistics and domain description. Theseresults indicate that the NOV6 polypeptide has properties similar tothose of other proteins known to contain these domains. TABLE 6F DOMAINANALYSIS OF NOV6 Score E PSSMs Producing Significant Alignments (bits)Value Phosphatidylinositol-specific phospholipase 264.3 1.6e−75(PI-PLC)-X: domain 1 of 1, from 288 to 433dmsiPLsHYfisSshntYLtgkQlwGkssvesYrqqLdaGcRcvELD (SEQ ID NO: 119)||++||+||+++|++++||+ +|++|++++++| +   +|+|++||| NOV6DMNQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDcwdGkpddepiIyHGhtltleiklkdVleaIkdfafkPtSpyPvIlSlen|| | + +||+|+||||||+++++ +|++|++++|++ +|++|+||||||CWEG-PGGEPVIYHGHTLTSKILFRDVVQAVRDHAFT-VSPYPVILSLENHcnsddqQrkmakyfkeiFgdmLltkPtlds.lttepglpLPslkdlrgK||  + ||+ ||+++ +|+||||+|   |||+ ++|++++|||+++|+|+HCGLE-QQAAMARHLCTILGDMLVTQA-LDSpNPEE----LPSPEQLKGR ILLknkk +|+|+||VLVKGKK PI-PLC-Y: domain 2 of 2, from 512 to 591 162.0 1e−44kllkespvefVkyNkrqLsRvYPkGtRvDSSNfmPqvfWnaGCQmVA (SEQ ID NO: 120)+|||+ +++||++| ||| |||| |+|+ | |++||++|| |||+|| NOV6RLLKAWGNSFVRHNARQLTRVYPLGLRMNSANYSPQEMWNSGCQLVALNfQTsDlpmqiNdGmFeyNggqPdGsfksGYlLKPeflR|||||++ +|++| |+|+ ||+       +||+|||++||LNFQTPGYEMDLNAGRFLVNGQ-------CGYVLKPACLR C2: domain 1 of 1, from 609 to699 89.5 6.7e−23 LtVtvieArnLpkmDk..vngrlsDPYVkvsllgdkkdlkkfkTkvv (SEQ IDNO:121) |++ |+ |++|||++ +++ + ++|| |+++++|++ |  +++|  | NOV6LSIQVLTAQQLPKLNAekPHS-IVDPLVRIEIHGVPADCARQETDYVkktNGLNPvWneEtFvFekvplpelasktLrfaVyDedrfsrdDfiGqvt ++ |+||+|+  |++|+ + +||||   +||+| |+| +| +||+||+|LNN-GFNPRWG-QTLQFQ-LRAPELAL--VRFVVEDYDATSPNDFVGQFT

[0109] The NOV6 nucleic acid and protein disclosed in this invention areexpressed in at least the following tissues: brain and colon. Thisinformation was derived by determining the tissue sources of thesequences that were included in the invention including but not limitedto SeqCalling sources, Public EST sources, Literature sources, and/orRACE sources. The protein similarity information, expression pattern,and map location for the NOV6 protein and nucleic acid disclosed hereinsuggest that this protein may have important structural and/orphysiological functions characteristic of the phospholipase family.Therefore, the NOV6 nucleic acids and proteins of the invention areuseful in potential diagnostic and therapeutic applications and as aresearch tool. For example, the compositions of the present inventionwill have efficacy for treatment of patients suffering from: VonHippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis,ataxia-telangiectasia, leukodystrophies, behavioral disorders,addiction, anxiety, pain, neuroprotection, hemophilia, hypercoagulation,idiopathic thrombocytopenic purpura, immunodeficiencies, graft versushost disease, lymphedema, allergies and other diseases, disorders andconditions of the like.

[0110] The novel NOV6 nucleic acids and polypeptides of the invention,or fragments thereof, are useful in diagnostic applications, wherein thepresence or amount of the nucleic acid or the protein are to beassessed. These materials are further useful in the generation ofantibodies that bind immunospecifically to the novel substances of theinvention for use in therapeutic or diagnostic methods. These antibodiesmay be generated according to methods known to one ordinarily skilled inthe art, using prediction from hydrophobicity charts, as described inthe “Anti-NOVX Antibodies” section below.

[0111] The disclosed NOV6 protein of the invention has multiplehydrophilic regions, each of which can be used as an immunogen. The NOV6protein also has value in the development of a powerful assay system forfunctional analysis of various human disorders, which will help inunderstanding of pathology of the disease and development of new drugtargets for various disorders.

[0112] Phosphoinositide-specific phospholipase C (PLC) subtypes comprisea related group of multidomain phosphodiesterases that cleave the polarhead groups from inositol lipids. Activated by all classes of cellsurface receptors, these enzymes generate the ubiquitous secondmessengers inositol 1, 4, 5-trisphosphate and diacylglycerol. The formerprovokes a transient increase in intracellular free Ca(2+), while thelatter serves as a direct activator of protein kinase C. Increase inintracellular Ca(2+) level and activated protein kinase C will furtheractivate distinct signal transduction pathways, which induce variousbiological responses, e.g., cell proliferation and the immune response.Therefore, phospholipases are important membrane bound enzymes that maypotentially serve as therapeutic drug targets.

[0113] NOV7

[0114] The NOV7 nucleic acid (SEQ ID NO:13) (alternatively referred toas CG55802-01) of 1059 nucleotides encodes a novel 3 alpha-hydroxysteroid dehydrogenase-like protein and is shown in Table 7A. An openreading frame for the mature protein was identified beginning with a ATGinitiation codon at nucleotides 31-33 and ending with a TAA codon atnucleotides 1000-1002. Putative untranslated regions upstream from thestart codon and downstream from the termination codon are underlined inTable 7A. The start and stop codons are in bold letters. TABLE 7A NOV7Nucleotide Sequence (SEQ ID NO:13) AAACATTTGCTAACCAGGCCAGTGACAGAAATGGATTCGAAATACCAGTGTGTGAAGCTGAATGATGGTCACTTCATGCCTGTCCTGGGATTTGGCACCTATGCGCCTGCAGAGGTACCTAAAAGTAAAGCTCTAGAGGCCGTCAAATTGGCAATAGAAGCCGGGTTCCACCATATTGATTCTGCACATGTTTACAATAATGAGGAGCAGGTTGGACTGGCCATCCGAAGCAAGATTGCAGATGGCAGTGTGAAGAGAGAAGACATATTCTACACTTCAAAGCTTTGGAGCAATTCCCATCGACCAGAGTTGGTCCGACCAGCCTTGGAAAGGTCACTGAAAAATCTTCAATTGGACTATGTTGACCTCTATCTTATTCATTTTCCAGTGTCTGTAAAGCCAGGTGAGGAAGTGATCCCAAAAGATGAAAATGGAAAAATACTATTTGACACAGTGGATCTCTGTGCCACATGGAAGGCCCTGGAGAAATGCAGAGATGCAGGTTTAACCAGGTCCATCAGGGTGTCCAGTTTCAATCACAAGCTGCTGGAACTCATCCTCAACAAGCCAGGGCTCAGGTACAAGCCCACCTGCAACCAGGTGGAATGTCACCCTTACCTCAACCAGAGCAAACTCCTGGAGTTCTGCAAGTCCAAGGACATTGTTCTAGTTGCCTACAGTGCCCTGGGATCCCAAAGAGACCCACAGTGGGTGGATCCCGACTGCCCACATCTCTTGGAGGAGCCGATCTTGAAATCCATTGCCAAGAAACACAGTCGAAGCCCAGGCCAGGTCGCCCTGCGCTACCAGCTGCAGCGGGGAGTGGTGGTGCTGGCCAAGAGCTTCTCTCAGGAGAGAATCAAAGAGAACTTCCAGGTATTTGACTTTGAGTTGACTCCAGAGGACATGAAAGCCATTGATGGCCTCAACAGAAATCTCCGATATCTTTCTTTCTTCAGTCTTGCTGGACACCCTGATTATCCATTTTCAGACAAATATTAA CATGGAGGACTTTGCGTGAGTTCTACCAGAGGCCCTGTGTGTAGATGGTGACACAGA

[0115] The NOV7 of the invention maps to chromosomes 10.

[0116] In a search of sequence databases, it was found, for example,that the NOV7 nucleic acid sequence of this invention has 940 of 1053bases (89%) identical to a gb:GENBANK-ID:HSU05598|acc:U05598.1 mRNA fromHomo sapiens (Human dihydrodiol dehydrogenase mRNA, complete cds).

[0117] The NOV7 polypeptide (SEQ ID NO: 14) encoded by SEQ ID NO: 13 is323 amino acid residues in length and is presented using the one-letteramino acid code in Table 7B. The SignalP, Psort and/or Hydropathyresults predict that NOV7 has no known signal peptide and is likely tobe localized in the cytoplasm with a certainty of 0.4500. In alternativeembodiments, a NOV7 polypeptide is located to the microbody (peroxisome)with a certainty of 0.3000, the mitochondrial matrix space with acertainty of 0.1000, or the lysosome (lumen) with a certainty of 0.1000.TABLE 7B Encoded NOV7 Protein Sequence (SEQ ID NO:14)MDSKYQCVKLNDGHFMPVLGFGTYAPAEVPKSKALEAVKLAIEAGFHHIDSAHVYNNEEQVGLAIRSKIADGSVKREDIFYTSKLWSNSHRPELVRPALERSLKNLQLDYVDLYLIHFPVSVKPGEEVIPKDENGKILFDTVDLCATWKALEKCRDAGLTRSIRVSSFNHKLLELILNKPGLRYKPTCNQVECHPYLNQSKLLEFCKSKDIVLVAYSALGSQRDPQWVDPDCPHLLEEPILKSIAKKHSRSPGQVALRYQLQRGVVVLAKSFSQERIKENFQVFDFELTPEDMKAIDGLNRNLRYLSFFSLAGHPDYPFSDKY

[0118] The full amino acid sequence of the NOV7 protein of the inventionhas 272 of 323 amino acid residues (84%) identical to, and 302 of 323amino acid residues (93%) similar to, the 323 amino acid residueptnr:TREMBLNEW-ACC:BAA36169 protein from Homo sapiens (Human) (DD2/BILEACID-BINDING PROTEIN/AKR1C2/3ALPHA-HYDROXYSTEROID DEHYDROGENASE TYPE 3).

[0119] The amino acid sequence of NOV7 has high homology to otherproteins as shown in Table 7C. TABLE 7C NOV7 BLASTP Results Gene LengthIndex/ of Identity Expect Identifier Protein/Organism aa (%) Positives(%) Value A96A71 ALDO-KETO REDUCTASE FAMILY 1467 272/323 (84%) 302/323(93%) 5.4e-150 1, MEMBER C2 (DIHYDRODIOL DEHYDROGENASE 2, BILE ACIDBINDING PROTEIN, 3-ALPHA HYDROXYSTEROID DEHYDROGENASE, TYPE III)(DD2/BILE ACID-BINDING PROTEIN/AKR1C2/3ALPHA- HYDROXYSTEROIDDEHYDROGENASE TYPE 3) - Homo sapiens (Human) P52895 Probabletrans-1,2-dihydrobenzene- 1453 269/323 (83%) 301/323 (93%) 1.7e-1481,2-dial dehydrogenase (EC 1.3.1.20) (Chlordecone reductase homologHAKRD) (Dihydrodiol dehydrogenase/bile acid-binding protein) (DD/BABP) -Homo sapiens (Human) Q04828 Trans-1,2-dihydrobenzene-1,2-diol 1432266/323 (82%) 297/323 (91%) 2.8e-146 dehydrogenase (EC 1.3.1.20) (High-affinity hepatic bile acid-binding protein) (EBAB) (Chlordecone 1432reductase homolog HAKRC) (Dihydrodiol dehydrogenase 2) (DD2) (20alpha-hydroxysteroid dehydrogenase) - Homo sapiens (Human) I53872dihydrodiol dehydrogenase (EC 1403 259/307 (84%) 290/307 (94%) 3.3e-1431.1.1.-) - human Q95JH6 3(20)ALPHA- 1398 257/323 (79%) 295/323 (91%)1.1e-142 HYDROXYSTEROID/DIHYDRODIOL/INDANOL DEHYDROGENASE (EC1.1.1.112) - Macaca fuscata (Japanese macaque)

[0120] A multiple sequence alignment is given in Table 7D in a ClustalWanalysis comparing NOV7 with related protein sequences disclosed inTable 7C.

[0121] Additional BLASTP results are shown in Table 7E. TABLE 7E PatpBLASTP Analysis for NOV7 Sequences producing High- scoring SegmentLength Identity Positive Pairs Protein/Organism (aa) (%) (%) E Valuepatp:AAB43444 Human cancer 336 266/323 296/323 5.7e-146 associatedprotein (82%) (91%) sequence patp:AAW14799 Type 5 17-beta- 323 249/323287/323 1.5e-138 hydroxysteroid (77%) (88%) dehydrogenase-Homo sapienspatp:AAM78471 Human protein 323 249/323 287/323 1.5e-138 No. 1133 (77%)(88%) patp:AAM79455 Human protein No. 3101 325 249/323 287/323 1.5e-138(77%) (88%) patp:AAY41041 Human lung tumor 364 244/295 274/295 1.4e-133antigen L773P (82%) (92%)

[0122] Domain results for NOV7 were collected from the Pfam database,and then identified by the Interpro domain accession number. The resultsare listed in Table 7F with the statistics and domain description. Theseresults indicate that the NOV7 polypeptide has properties similar tothose of other proteins known to contain these domains. TABLE 7F DOMAINANALYSIS OF NOV7 Score E PSSMs Producing Significant Alignments (bits)Value aldo_ket_red: domain 1 of 1, from 10 to 303 502.7 5.7e−149LnnGlklkmPllGlGtwqtpgeedylwgrvdkeeakeavkaAldaGY (SEQ ID NO: 127)||+|+  +||+||+||+ + +        |+|  | |||| |++||+ NOV7LNDGH--FMPVLGFGTYAPAE--------VPKSKALEAVKLAIEAGFRhiDtAaiYgNGqkPgqSEeevGeaikealeegsvvvitkykRediFits |||++           ||+||+||++++++|||      ||||||+||HHIDSAHVYNN-------EEQVGLAIRSKIADGSV------KREDIFYTSdKlwntfgpDlseyghspkhvrealekSLkrLgLdYvDLyLiHwPdpfkp||| ++        |+|++||+||| |||+|+||||||||||+|++||-KLWSNS--------HRPELVRPALERSLKNLQLDYVDLYLIHFPVSVKPgiedkyplgfptdddgkliyedvpieetWkAleklvdeGkvrslGVSNfs ||+     +|+|++||+++++|++++|||||||++|+|++||| ||+|+G-EEV----IPKDENGKILFDTVDLCATWKALEKCRDAGLTRSIRVSSFNaeqleellsyagklklipPvvnQvElHPylrqdelrkvPLLpfCkShGIa ++ || +|+++| |+++|++||||+||||+| +|++     ||||++|+NKLLELILNKPG-LR-YKPTCNQVECHPYLNQSKLLE-----FCKSKDIVvtAySPLgsGlLtGkykteedipgdrrsllgadkgwselgspelledpvl ++||||||++                     | +|++++ | |||+|+|LVAYSALGSQR---------------------DPQWVDPDCPHLLEEPILkaiAekygykdktpAQvaLrWalqrGgGagvvvvIPKSsnpeRikeNlka | ||+|+    ++||||||++||||     |||++||++ ||||||+++KSIAKKHS---RSPGQVALRYQLQRG-----VVVLAKSFSQERIKENFQV fddfeLteedmkaideldrgk| |||||+|||||||+|+|+ F-DFELTPEDMKAIDGLNRNL

[0123] The NOV7 nucleic acids and polypeptides disclosed in thisinvention are expressed in at least the following tissues: liver/spleen(pool), and gall bladder. This information was derived by determiningthe tissue sources of the sequences that were included in the inventionincluding but not limited to SeqCalling sources, Public EST sources,Literature sources, and/or RACE sources.

[0124] The protein similarity information, expression pattern, and maplocation for the NOV7 protein and nucleic acid disclosed herein suggestthat this protein may have important structural and/or physiologicalfunctions characteristic of the aldo-keto reductase family. Therefore,the NOV7 nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications and as a researchtool. For example, the compositions of the present invention will haveefficacy for treatment of patients suffering from: cancer, trauma,regeneration (in vitro and in vivo), viral/bacterial/parasiticinfections, Von Hippel-Lindau (VHL) syndrome, cirrhosis, transplantationand other diseases, disorders and conditions of the like.

[0125] The novel NOV7 nucleic acids and polypeptides of the invention,or fragments thereof, are useful in diagnostic applications, wherein thepresence or amount of the nucleic acid or the protein are to beassessed. These materials are further useful in the generation ofantibodies that bind immunospecifically to the novel substances of theinvention for use in therapeutic or diagnostic methods. These antibodiesmay be generated according to methods known to one ordinarily skilled inthe art, using prediction from hydrophobicity charts, as described inthe “Anti-NOVX Antibodies” section below.

[0126] The disclosed NOV7 protein of the invention has multiplehydrophilic regions, each of which can be used as an immunogen. The NOV7protein also has value in the development of a powerful assay system forfunctional analysis of various human disorders, which will help inunderstanding of pathology of the disease and development of new drugtargets for various disorders.

[0127] The aldo-keto reductase family includes a number of relatedmonomeric NADPH-dependent oxidoreductases, such as aldose reductase,prostaglandin F synthase, xylose reductase, aldehyde reductases,hydroxysteroid dehydrogenases, dihydrodiol dehydrogenases and manyothers. All possess a similar structure, with a beta-alpha-beta foldcharacteristic of nucleotide binding proteins. The fold comprises aparallel beta-8/alpha-8-barrel, which contains a novel NADP-bindingmotif. The (alpha/beta) 8-barrel fold provides a common scaffold for anNAD(P)(H)-dependent catalytic activity, with substrate specificitydetermined by variation of loops on the C-terminal side of the barrel.All the aldo-keto reductases are dependent on nicotinamide cofactors forcatalysis and retain a similar cofactor binding site, even amongproteins with less than 30% amino acid sequence identity. Members ofmembers of the aldo-keto reductase (AKR), short-chaindehydrogenases/reductases (SDR) and quinone reductase (QR) superfamiliesare involved in reductive pathways involved in synthesis and dispositionof carbonyl and hydroxyl group containing compounds.

[0128] NOV8

[0129] A disclosed NOV8 nucleic acid (SEQ ID NO:15) of 879 nucleotides(also referred to as CG55904-01) encoding a novel SqualeneDesaturase-like protein is shown in Table 8A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 24-26and ending with a TGA codon at nucleotides 861-863. Putativeuntranslated regions are found upstream from the initiation codon anddownstream from the termination codon, and are underlined. The start andstop codons are shown in bold letters in Table 8A. TABLE 8A NOV8nucleotide sequence. (SEQ ID NO:15) ATTATAACTATTGTCACAATATAATGAAAGAACATTCAAAAACGTTCTCATATGCCTTTGATTTTTTGGATTTAAAAAGGAAAAAAGCAATTTGGGCTATTTATGCAGTTTGCAGAATTATAGATGACAGTATTGATAAATACAAAGACCTTGAGCAATTAAACGGCATAGCTAGAGATTTAGATGTGATTTATAGCGATTGTGATTATATTCAAGCCTATCAAAGTGATGCAGCTATTATGAATGCTTTAAGTAATACATTGAATACATATTCAATACCTAAAAAACCTTTTGAATCTTTAATTCAATATGTGAAGGAAGATTTAGTTTTAAAAGAAATGAAAACTGATTCAGATTTATATGAGTATTGCTATGGTGTGGTAGGTACTGTCGGTGAATTGTTAACTCCTATATTAACTTCATCAAATGAAAATAATTTCGAGCAAGCTGAAGAAGCTGCGATTGCTTTAGGCAAGGCAATGCAAATAACTAATATTTTAAGAGATGTCGGCGAAGATTTTCAAAATGGAAGAATTTATCTAAGTGTTGAAAAATTAGCTCAATATCGAGTTAATCTACATTCTATATATTATGAAGGAGTTTCGCCAAATTATATAGAACTGTGGGAAAGTTACGCTACAGAGACAGTTAGGTTATATGATATTGCATTAAACGGTATTAATTATTTTGACGAAGAGGTACGTTACATTATCGAATTAGCTGCGATAGCTTATCATGAAATACTTGTGGAAGTAAGGAAGGCAAACTATACGTTGCATAAGAAAGTATATGTAAGCAAATTGAAAAAAATGAAAATTTATCGTGAACTTAGTGCGAAATATAATAGGAGTGAAACATTATGA AGATTGCAGTTATAGG

[0130] NOV8 CG55904-01 genomic clones map to chromosome 5.

[0131] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 532 of 879 bases(60%) identical to a gb:GenBank-ID:SAP1P2|acc:X73889.1 mRNA from genescrtM and crtN from S. aureus.

[0132] A disclosed NOV8 polypeptide (SEQ ID NO: 16) encoded by SEQ IDNO: 15 has 279 amino acid residues and is presented in Table 8B usingthe one-letter amino acid code. SignalP, Psort and/or Hydropathy resultspredict that NOV8 does not possess a signal peptide and is likely to belocalized to the cytoplasm with a certainty of 0.3000. NOV8 has amolecular weight of 32387.5 Daltons. TABLE 8B Encoded NOV8 proteinsequence. (SEQ ID NO:16)MKEHSKTFSYAFDFLDLKRKKAIWAIYAVCRIIDDSIDKYKDLEQLNGIARDLDVIYSDCDYIQAYQSDAAIMNALSNTLNTYSIPKKPFESLIQYVKEDLVLKEMKTDSDLYEYCYGVVGTVGELLTPILTSSNENNFEQAEEAAIALGKAMQITNILRDVGEDFQNGRIYLSVEKLAQYRVNLHSIYYEGVSPNYIELWESYATETVRLYDIALNGINYFDEEVRYIIELAAIAYHEILVEVRKANYTLHKKVYVSKLKKMKIYRELSAKYNRSETL

[0133] The full amino acid sequence of the protein of the invention wasfound to have 133 of 275 amino acid residues (48%) identical to, and 183of 275 amino acid residues (66%) similar to, the 287 amino acid residueptnr:SptrEmbl-ACC:Q99R75 Squalene Desaturase protein from S. aureus.

[0134] In a further search of public sequence databases, NOV8 was foundto have homology to the amino acid sequences shown in the BLASTP datalisted in Table 8C. TABLE 8C BLASTP results for NOV8 Posi- Gene Index/Length Identity tives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SPTREMBL- SQUALENE DESATUXASE - 287 133/275 183/275 1.7e-61ACC:Q99R75 Staphylococcus aureus (48%) (66%) ptnr:SPTREMBL- SQUALENEDESATURASE - 255 113/241 151/241 2.9e-48 ACC:O07854 Staphylococcusaureus (46%) (62%) ptnr:pir- crtM protein - 254 104/241 143/241 4.1e-42id:A55548 Staphylococcus aureus (43%) (59%) ptnr:SPTREMBL- PEYTOENESYNTHASE - 436 85/261 138/261 3.0e-30 ACC:Q9M608 Citrus unshiu (32%)(52%) ptnr:SWISSNEW- Phytoene synthase, 410 89/262 145/262 1.0e-29ACC:P49085 chloroplast precursor (33%) (55%)

[0135] The homology of these sequences is shown graphically in theClustalW analysis shown in Table 8D. NOV8 polypeptide is provided inlane 1.

[0136] BLAST analysis was performed on sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 8E. TABLE 8E Patp BLASTP Analysis for NOV8 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAY44217 Soybean phytoene 400 85/261 136/2613.8e-30 synthase - Glycine max (32%) (52%) patp:AAY84101 Amino acidsequence of 412 85/261 137/261 1.3e-29 a phytoene synthase (32%) (52%)polypeptide - Lycopersicon esculentum patp:AAW41057 Phytoene synthasefrom 410 83/261 137/261 9.Oe-29 N. benthamiana - (31%) (52%) Nicotianabenthamiana patp:AAG10658 Arabidopsis thaliana 422 83/261 134/2611.2e-28 protein fragment SEQ (31%) (51%) ID NO: 9068 - Arabidopsisthaliana patp:AAG10659 Arabidopsis thaliana 403 83/261 134/261 1.2e-28protein fragment SEQ (31%) (51%) ID NO: 9069 - Arabidopsis thaliana

[0137] DOMAIN results for NOV8 as disclosed in Tables 8F, were collectedfrom the Conserved Domain Database (CDD) with Reverse Position SpecificBLAST analyses. This BLAST analysis software samples domains found inthe Smart and Pfam collections.

[0138] Table 8F lists the domain description from DOMAIN analysisresults against NOV8. This indicates that the NOV8 sequence hasproperties similar to those of other proteins known to contain thesedomains. TABLE 8F Domain Analysis of NOV8 PSSMs producing significantalignments: Score (bits) E value SQS_PSY (InterPro) Squalene/phytoenesynthase 130.7 2.1e−35 SQS_PSY: domain 1 of 2, from 1 to 38: score 21.0,E = 8e−05 laqgSkSFalairLlppelRravlalYlwCRaaDdvVD<-* (SEQ ID NO: 132)+ ++||+|  |   |+ ++ +|++|+|++||  || +| NOV8 1MKEHSKTFSYAFDFLDLKRKKAIWAIYAVCRIIDDSID 38 SQS_PSY: domain 2 of 2, from69 to 262: score 109.7, E = 1.5e−29DapvdraFaPCAYqALdvleefdiprepfrdlIedIkrMGaGmamD (SEQ ID NO: 133)|| ++ |++        +| ++ ||++||+ ||            | NOV8 69DAAIMNALS-------NTLNTYSIPKKPFESLIQ-------YVKED 100lekreknlqyryatfeDllrYCyyVAGtVGlmmarlmgvrkledpAdwql|           +|++||++|||+| ||||+++++++  ++ ++ 101LVLK------EMKTDSDLYEYCYGVVGTVGELLTPILTSSNENNF----- 139eevldlrAcdLGLAlQLTNIaRDvgEDarrGPCRvYLPtewLsqYGlsle| +++ +|++|| |+| |||+||||||++ |  |+||  | |+|| ++| 140EQAEE-AAIALGKAMQITNILRDVGEDFQNG--RIYLSVEKLAQYRVNLH 186dllapentdkrirrvlrrlldnArayyedAltGlagLppqsrfpiaAApq+ ++ +++  + ++ +  +++  ++|+ || |+    ++ |  |  |+ 187SIYYEGVSPN-YIELWESYATETVRLYDIALNGINYFDEEVRYIIELAAI 235vYagIgdaieangydvfrrRaktrkgek<* | +|++++++++| ++++ ++++| +| 236AYHEILVEVRKANY-TLHKKVYVSKLKK 262

[0139] NOV8 is expressed in at least the following tissues: colon,brain, lung, lumph, and tonsil (enriched for germinal center b-cells).

[0140] Squalene synthase (famesyl-diphosphate famesyltransferase)(SQS)belongs to the squalene and phytoene synthases family. Phytoene synthase(PSY) catalyzes the conversion of two molecules of geranylgeranyldiphosphate (GGPP) into phytoene. The reaction carried out by PSY iscatalyzed in two separate steps: the first is a head-to-headcondensation of the two molecules of GGPP to form prephytoenediphosphate; this intermediate is then rearranged to form phytoene. psyis found in all organisms that synthesize carotenoids: plants andphotosynthetic bacteria as well as some non-photosynthetic bacteria andfungi. In bacteria PSY is encoded by the gene CTRB. In plants PSY islocalized in the chloroplast.

[0141] As it can be seen from the description above, both SQS and PSYshare a number of functional similarities which are also reflected atthe level of their primary structure. In particular three well conservedregions are shared by SQS and PSY; they could be involved in substratebinding and/or the catalytic mechanism. Squalene synthase(farnesyl-diphosphate farnesyltransferase)(SQS) and Phytoene synthase(PSY) share a number of functional similarities. These similarities arealso reflected at the level of their primary structure. In particular,three well conserved regions are shared by SQS and PSY; they could beinvolved in substrate binding and/or the catalytic mechanism. Squalenesynthase (farnesyl-diphosphate farnesyltransferase)(SQS) catalyzes theconversion of two molecules of farnesyl diphosphate (FPP) into squalene.It is the first committed step in the cholesterol biosynthetic pathway.The reaction carried out by SQS is catalyzed in two separate steps: thefirst is a head-to-head condensation of the two molecules of FPP to formpresqualene diphosphate; this intermediate is then rearranged in aNADP-dependent reduction, to form squalene: 2 FPP->presqualenediphosphate+NADP->squalene SQS is found in eukaryotes. In yeast is isencoded by the ERG9 gene, in mammals by the FDFT1 gene.

[0142] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients such as: Obesity, dietary disorders, VonHippel-Lindau (VHL) syndrome, Alzheimer's disease, Stroke, Tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,Cerebral palsy, Epilepsy, Lesch-Nyhan syndrome, Multiple sclerosis,Ataxia-telangiectasia, Leukodystrophies, Behavioral disorders,Addiction, Anxiety, Pain, Neuroprotection, Tonsilitis, Lymphedema,Allergies, Systemic lupus erythematosus, Autoimmune disease, Asthma,Emphysema, Scleroderma, allergies, ARDS and other diseases, disordersand conditions of the like.

[0143] As described earlier, NOV8 shares extensive sequence homologieswith Squalene Desaturase family proteins. The structural similaritiesindicate that NOV8 may function as a member of Squalene Desaturasefamily proteins. Accordingly, the NOV8 nucleic acids and proteinsidentified here may be useful in potential therapeutic applicationsimplicated in (but not limited to) various pathologies and disorders asindicated herein. For example, a cDNA encoding the SqualeneDesaturase-like protein NOV8 may be useful in gene therapy, and theSqualene Desaturase-like protein NOV8 may be useful when administered toa subject in need thereof. The NOV8 nucleic acid encoding SqualeneDesaturase-like protein, and the Squalene Desaturase-like protein of theinvention, or fragments thereof, may further be useful in diagnosticapplications, wherein the presence or amount of the nucleic acid or theprotein are to be assessed. Additional disease indications and tissueexpression for NOV8 and NOV8 variants, if available, are presented inthe Examples.

[0144] NOV8 nucleic acids and polypeptides are further useful in thegeneration of antibodies that bind immuno-specifically to the novel NOV8substances for use in therapeutic or diagnostic methods. Theseantibodies may be generated according to methods known in the art, usingprediction from hydrophobicity charts, as described in the “Anti-NOVXAntibodies” section below. The disclosed NOV8 protein has multiplehydrophilic regions, each of which can be used as an immunogen. In oneembodiment, a contemplated NOV8 epitope is from about amino acids 1 to35. In another embodiment, a NOV8 epitope is from about amino acids 50to 85. In additional embodiments, NOV8 epitopes are from about aminoacids 95 to 125, from about amino acids 175 to 200, from about aminoacids 215 to 325, and from about amino acids 335 to 711. These novelproteins can be used in assay systems for functional analysis of varioushuman disorders, which will help in understanding of pathology of thedisease and development of new drug targets for various disorders.

[0145] NOV9

[0146] A disclosed NOV9 nucleic acid (SEQ ID NO:17) of 939 nucleotides(also referred to as CG55954-01) encoding a novel Lymphocyte Antigen64-like protein is shown in Table 9A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 140-142and ending with a TAA codon at nucleotides 920-922. Putativeuntranslated regions are found upstream from the initiation codon anddownstream from the termination codon, and are underlined. The start andstop codons are shown in bold letters in Table 9A. TABLE 9A NOV9nucleotide sequence (SEQ ID NO:17)TTAGCAAGTCGCATTATCCTCACTAAAGGGAACAAAAGCTGGAGCTCCACCGCGGTGGCGGCCGCTCTAGAACTAGTGGATCCCCCGGGCTGCAGGAATTCGGCACGAGGGTAAACCCACCAAGCAATCCTAGCCTGTG ATGGCGTTTGACGTCAGCTGCTTCTTTTGGGTGGTGCTGTTTTCTGCCGGCTGTAAAGTCATCACCTCCTGGGATCAGATGTGCATTGAGAAAGAAGCCAACAAAACATATAACTGTGAAAATTTAGGTCTCAGTGAAATCCCTGACACTCTACCAAACACAACAGAATTTTTGGAATTCAGCTTTAATTTTTTGCCTACAATTCACAATAGAACCTTCAGCAATCAGCATCTTCTAGCAGGCCTACCAGTTCTCCGGCATCTCAACTTAAAAGGGAATCACTTTCAAGATGGGACTATCACGAAGACCAACCTACTTCAGACCGTGGGCAGCTTGGAGGTTCTGATTTTGTCCTCTTGTGGTCTCCTCTCTATAGACCAGCAAGCATTCCACAGCTTGGGAAAAATGAGCCATGTAGACTTAAGCCACAACAGCCTGACATGCGACAGCATTGATTCTCTTAGCCATCTTAAGGGAATCTACCTCAATCTGGCTGCCAACAGCATTAACATCATCTCACCCCGTCTCCTCCCTATCTTGTCCCAGCAGAGCACCATTAATTTAAGTCATAACCCCCTGGACTGCACTTGCTCGAATATTCATTTCTTAACATGGTACAAAGAAAACCTGCACAAACTTGAAGGCTCGGAGGAGACCACGTGTGCAAACCCGCCATCTCTAAGGGGAGTTAAGCTATCTACCTCAATCTGGCTGCCAACAGCATTAACATCATCTCACCCCGTCTCCTCCCTATCTTGTCCCAGCAGAGCACCATTAATTTAA GTCATAACCCCCTGGAA

[0147] NOV9 CG55954-01 genomic clones map to chromosome 5q12.

[0148] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 487 of 492 bases(98%) identical to a gb:GenBank-ID:D83597|acc:D83597.1 mRNA from Homosapiens (RP105, complete cds).

[0149] A disclosed NOV9 polypeptide (SEQ ID NO: 18) encoded by SEQ IDNO: 17 has 260 amino acid residues and is presented in Table 9B usingthe one-letter amino acid code. NOV9 has an INTEGRAL Likelihood of −2.39that it is a transmembrane protein. SignalP, Psort and/or Hydropathyresults predict that NOV9 has a signal peptide and is likely to belocalized to the plasma membrane with a certainty of 0.4600. The mostlikely cleavage site for a NOV9 peptide is between amino acids 23 and24, i.e., at the dash between amino acids ITS-WD. NOV9 has a molecularweight of 28738.5 Daltons. TABLE 9B Encoded NOV9 protein sequence. SEQID NO:18MAFDVSCFFWVVLFSAGCKVITSWDQMCIEKEANKTYNCENLGLSEIPDTLPNTTEFLEFSFNFLPTIHNRTFSNQHLLAGLPVLRHLNLKGNHFQDGTITKTNLLQTVGSLEVLILSSCGLLSIDQQAFHSLGKMSHVDLSHNSLTCDSIDSLSHLKGIYLNLAANSINIISPRLLPILSQQSTINLSHNPLDCTCSNIHFLTWYKENLHKLEGSEETTCANPPSLRGVKLSTSIWLPTALTSSHPVSSLSCPSRAPLI

[0150] The full amino acid sequence of the protein of the invention wasfound to have 166 of 189 amino acid residues (87%) identical to, and 172of 189 amino acid residues (91%) similar to, the 661 amino acid residueptnr:SptrEmbl-ACC:Q99467 Lymphcyte Antigen 64 precursor protein fromHomo sapiens.

[0151] In a further search of public sequence databases, NOV9 was foundto have homology to the amino acid sequences shown in the BLASTP datalisted in Table 9C. TABLE 9C BLASTP results for NOV9 Posi- Gene Index/Length Identity tives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SPTREMBL- LYMPHOCYTE ANTIGEN 64 661 166/189 172/189 8.3e-83ACC:Q99467 PRECURSOR (RP105) - (87%) (91%) Homo sapiens ptnr:SPTREMBL-LYMPHOCYTE ANTIGEN 78 661 111/160 128/160 1.4e-55 ACC:Q62192 PRECURSOR(RP105) - (69%) (80%) Mus musculus

[0152] The homology of these sequences is shown graphically in theClustalW analysis shown in Table 9D. NOV9 polypeptide is provided inlane 1.

[0153] BLAST analysis was performed on sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 9E. TABLE 9E Patp BLASTP Analysis for NOV9 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAW28510 Product of clone J422 - 661 166/189172/189 6.4e-83 Homo sapiens (87%) (91%) patp:AAW87556 B cell surfaceprotein 661 166/189 172/189 6.4e-83 sequence - (87%), (91%) Homo sapienspatp:AAY82527 Human RP105 protein 650 166/189 172/189 6.4e-83 sequence(87%) (91%) patp:AAW47274 Human B-cell 661 163/189 169/189 1.1e-80activation and (86%) (89%) survival antigen-1 patp:AAY11833 Human 5′ ESTsecreted  75 72/74 72/74 1.2e-35 protein (97%) (97%)

[0154] DOMAIN results for NOV9 as disclosed in Tables 9F, were collectedfrom the Conserved Domain Database (CDD) with Reverse Position SpecificBLAST analyses. This BLAST analysis software samples domains found inthe Smart and Pfam collections. Table 9F lists the domain descriptionfrom DOMAIN analysis results against NOV9. TABLE 9F Domain Analysis ofNOV9 PSSMs producing significant alignments: Score (bits) E value LRRCT(InterPro) Leucine rich repeat C-terminal domain 44.4 2.6e−09 LRR(InterPro) Leucine Rich Repeat 28.8 0.00013 LRR: domain 1 of 4, from 54to 77: score 4.2, E = 1.7e +02 nLeeLdLsnNnLsGslPpesfgnLp<-* (SEQ IDNO:136)   |+|  |+| |  ++++ +|+| + NOV9 54 TTEFLEFSFNFLP-TIHNRTFSNQH 77LRR: domain 2 of 4, from 84 to 107: score 4.1, E =010 1.7e +02nLeeLdLsnNnLs.GslPpesfgnLp<-* (SEQ ID NO:137) |++|+| +|++++|++       |+NOV9 84 VLRELNLKGNHFQdGTITK--TNLLQ 107 LRR: domain 3 of 4, from 111 to134: score 16.6, E =0.59 nLeeLdLSnNnLsGslPpesfgnLp<-* (SEQ ID NO:138)+||+| ||++ |  |+ +++| +| NOV9 111 SLEVLILSSCGLL-SIDQQAFHSLG 134 LRR:domain 4 of 4, from 135 to 158: score 14.0, E = 3.7nLeeLdLsnNnLsGslPpesfgnLp<-* (SEQ ID ID:139) +  + |||+|+|+   + +|+++|+NOV9 135 KMSHVDLSHNSLT-CDSIDSLSHLK 158 LRRCT: domain 1 of 1, from 191 to254: score 44.4, E = 2.6e−09NpfnCDCeLrwLlrWlretnprrledqedlrCasPeslrGqpl.... (SEQ ID NO:140)||++|+|+   +|+| +| |  +||++|+++||+|+|||| +|+++ NOV9 191NPLDCTCSNIHFLTWYKE-NLHKLEGSEETTCANPPSLRGVKLstsi .....lellp..sdfsCp<-*  ++ |+ +++ |++||| 237 wlptaLTSSHpvSSLSCP 254

[0155] Lymphocyte antigen 64 (RP105) is a B cell Toll like receptor(TLR) that transmits a growth-promoting signal and is implicated in thelife/death decision of B cells. The growth-promoting signal activationby RP105 leads to resistance against irradiation-induced apoptosis andmassive B-cell proliferation. RP105 has tandem repeats of a leucine-richmotif in the extracellular domain that is expected to be involved inprotein-protein interactions. Role of RP105 has been implicated not onlyin B cell proliferation but also in secretion of large quantities ofLPS-neutralizing antibodies as an innate immune responses to bacterialcell wall lipopolysaccharide. Loss of RP105 has been implicated inincreased disease activity in systemic lupus erythematosus.

[0156] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from: bacterial infection, allergicdisease such as asthma, B cell neoplasms, auto-immune diseases such assystemic lupus erythematosus (SLE), histocystic leukemia, hairy cellleukaemia, prolymphocytic leukaemia, myelomas and other diseases,disorders and conditions of the like.

[0157] NOV9 shares extensive sequence homologies with Lymphocyte Antigen64 family proteins. The structural similarities indicate that NOV9 mayfunction as a member of Lymphocyte Antigen 64 family proteins.Accordingly, the NOV9 nucleic acids and proteins identified here may beuseful in potential therapeutic applications implicated in (but notlimited to) various pathologies and disorders as indicated herein. Forexample, a cDNA encoding the Lymphocyte Antigen 64-like protein NOV9 maybe useful in gene therapy, and the Lymphocyte Antigen 64-like proteinNOV9 may be useful when administered to a subject in need thereof. TheNOV9 nucleic acid encoding Lymphocyte Antigen 64-like protein, and theLymphocyte Antigen 64-like protein of the invention, or fragmentsthereof, may further be useful in diagnostic applications, wherein thepresence or amount of the nucleic acid or the protein are to beassessed.

[0158] The Lymphocyte Antigen 64 disclosed in this invention isexpressed in at least the following tissues: Adrenal gland, bone marrow,brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantianigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetalliver, fetal lung, heart, kidney, lymphoma—Raji mammary gland, pancreas,pituitary gland, placenta, prostate, salivary gland, skeletal muscle,small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea,uterus. Based on the tissues in which NOV9 is most highly expressed,specific uses include developing products for the diagnosis or treatmentof a variety of diseases and disorders associated therewith. Additionalspecific expression of NOV9 in normal and diseased tissues are shown inthe Examples.

[0159] NOV9 nucleic acids and polypeptides are further useful in thegeneration of antibodies that bind immuno-specifically to the novel NOV9substances for use in therapeutic or diagnostic methods. Theseantibodies may be generated according to methods known in the art, usingprediction from hydrophobicity charts, as described in the “Anti-NOVXAntibodies” section below. The disclosed NOV9 protein has multiplehydrophilic regions, each of which can be used as an immunogen. In oneembodiment, a contemplated NOV9 epitope is from about amino acids 1 to35. In another embodiment, a NOV9 epitope is from about amino acids 50to 85. In additional embodiments, NOV9 epitopes are from about aminoacids 95 to 125, from about amino acids 175 to 200, from about aminoacids 215 to 325, and from about amino acids 335 to 711. These novelproteins can be used in assay systems for functional analysis of varioushuman disorders, which will help in understanding of pathology of thedisease and development of new drug targets for various disorders.

[0160] NOV10

[0161] A disclosed NOV10 nucleic acid (SEQ ID NO:19) of 2349 nucleotides(also referred to as CG55910-01) encoding a novel ACYL-COADESATURASE-like protein is shown in Table 10A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 260-262and ending with a TGA codon at nucleotides 1250-1252. Putativeuntranslated regions are found upstream from the initiation codon anddownstream from the termination codon, and are underlined. The start andstop codons are shown in bold letters in Table 10A. TABLE 10A NOV10nucleotide sequence. (SEQ ID NO:19)TATTTTAATCCCCCCCCCCCCCCGAGCCATATGGGGGATACGCCAGCAACAGACGCCGGCCGCCAAGATCTGCATCCCTAGGCCACGCTAAGACCCTGGGGAAGAGCGCAGGAGCCCGGGAGAAGGGCTGGAAGGAGGGGACTGGACGTGCGGAGAATTCCCCCCTAAAAGGCAGAAGCCCCCGCCCCCACCCTCGAGCTCCGCTCGGGCAGAGCGCCTGCCTGCCTGCCGCTGCTGCGGGCGCCCACCTCGCCCA GCCATGCCAGGCCCGGCCACCGACGCGGGGAAGATCCCTTTCTGCGACGCCAAGGAAGAAATCCGTGCCGGGCTCGAAAGCTCTGAGGGCGGCGGCGGCCCGGAGAGGCCAGGCGCGCGCGGGCAGCGGCAGAACATCGTCTGGAGGAATGTCGTCCTGATGAGCTTGCTCCACTTGGGGGCCGTGTACTCCCTGGTGCTCATCCCCAAAGCCAAGCCACTCACTCTGCTCTGGGCCTACTTCTGCTTCCTCCTGGCCGCTCTGGGTGTGACAGCTGGTGCCCATCGCTTGTGGAGCCACAGGTCCTACCGGGCCAAGCTGCCTCTGAGGATATTTCTGGCTGTCGCCAACTCCATGGCTTTCCAGAATGACATCTTCGAGTGGTCCAGGGACCACCGAGCCCACCACAAGTACTCAGAGACGGATGCTGACCCCCACAATGCCCGCCGGGGCTTCTTCTTCTCCCATATTGGGTGGCTGTTTGTTCGCAAGCATCGAGATGTTATTGAGAAGGGGAGAAAGCTTGACGTCACTGACCTGCTTGCTGATCCTGTGGTCCGGATCCAGAGAAAGTACTATAAGATCTCCGTGGTGCTCATGTGCTTTGTGGTCCCCACGCTGGTGCCCTGGTACATCTGGGGAGAGAGTCTGTGGAATTCCTACTTCTTGGCCTCTATTCTCCGCTATACCATCTCACTCAACATCAGCTGGCTGGTCAACAGCGCCGCCCACATGTATGGAAACCGGCCCTATGACAAGCACATCAGCCCTCGGCAGAACCCACTCGTCGCTCTGGGTGCCATTGGTGAAGGCTTCCATAATTACCATCACACCTTTCCCTTTGACTACTCTGCGAGTGAATTTGGCTTAAATTTTAACCCAACCACCTGGTTCATTGATTTCATGTGCTGGCTGGGGCTGGCCACTGACCGCAAACGGGCAACCAAGCCGATGATCGAGGCCCGGAAGGCCAGGACTGGAGACAGCAGTGCTTGA ACTTGGAACAGCCATCCCACATGTCTGCCGTTGCAACCTCGGTTCATGGCTTTGGTTACAATAGCTCTCTTGTACATTGGATCGTGGGAGGGGGCAGAGGGTGGGGAAGGAACGAGTCAATGTGGTTTGGGAATGTTTTTGTTTATCTCAAAATAATGTTGAAATACAATTATCAATGAAAAAACTTTCGTTTTTTTTTTTGGTTGGTTTTGTTTTTGAGACAGAGTCTCACTCTGTCACCCAGGCTGGAGTGCAGTGGCGCAGTCTCGGCTCACTGCAGCCTCCACCTACCTGGTTCAAGCAATTCTCCTGCCTCAGCCTCCTGAGTAGCTGAGATTACAGGAGCCTGCCACCACACCCAGCTAATTTTTTTGTATTTTTAGTAGAGACAGGGTTTCATCATGTTGGCCAGACTGGCCTCGAATTCCTGACCTCAGGCAATCCACCCGCCTCGGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCACCCTGCCGAAAAAAACTTTTTTTTTTTGAGACGGAGGCTCGCTCTGTCCCCCAGGTCTGGATGTGCAGTGGCGAGATTTCAGCTCACTGACAAGCTCCGCCTCCCGGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGGAGCCAGCGCGCCCAGCCTAAAAAACTTTTCAGGTCAATATTACTACGATTTAACTTTACGAGTGTGGACCTGTGATTTAATCGGCTATTAGCTAAGAATAGCGTCAAATTATTCGTGTGTCATTGTGGCTTGAACATTGATGGCTAACCCTTCCTGGAAAGGGATGAAGGCAAAGTAATATTTCTTTTAGTGGTAGTTCAGGAGACCATGTGGTCTCCTTTGTCTACCAATTTACCCGATCATGTGTTATTAAAACACCCCTTCTGGAGGACAAAGAGGGGTTACACACACAGGGGTCTTGTCGGGCAACACAGCAGGTCCGGTGACCATCGGGCGGCGGGGTCTCGCGGCTCCAACTCACCCGGCACACACGACAACAGACGGGCTGATCTCGGGGTACCGGAAGCCTCGTCGAAACAAATATCGCCGTTTTGCTCGACGCCAAACTGCTAT

[0162] The ACYL-COA DESATURASE NOV10 disclosed in this invention maps tochromosome 4.

[0163] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 805 of 808 bases(99%) identical to a gb:GENBANK-ID:AK024685|acc:AK024685.1 mRNA fromHomo sapiens (Homo sapiens cDNA: FLJ21032 fis, clone CAE07365).

[0164] A disclosed NOV10 polypeptide (SEQ ID NO:20) encoded by SEQ IDNO:19 has 330 amino acid residues and is presented in Table 10B usingthe one-letter amino acid code. SignalP, Psort and/or Hydropathy resultspredict that NOV10 has a signal peptide and is likely to be localizedextracellularly with a certainty of 0.6000. In an alternativeembodiment, NOV10 is likely to be localized to the Golgi with acertainty of 0.4000, or to the endoplasmic reticulum (membrane) with acertainty of 0.3000, or to the microbody (peroxisome) with a certaintyof 0.3000. NOV10 is likely a Type IIIa membrane protein (Ncyt Cexo) andhas a likely cleavage site between pos. 16 and 17, i.e., at the dash inthe amino acid sequence CDA-KE. TABLE 10B Encoded NOV10 proteinsequence. (SEQ ID NO:20)MPGPATDAGKIPFCDAKEEIRAGLESSEGGGGPERPGARGQRQNIVWRNVVLMSLLHLGAVYSLVLIPKAXPLTLLWAYFCFLLAALGVTAGAHRLWSHRSYRAKLPLRIFLAVANSMAFQNDIFEWSRDHRAHHKYSETDADPHNARRGFFFSHIGWLFVRKHRDVIEKGRKLDVTDLLADPVVRIQRKYYKISVVLMCFVVPTLVPWYIWGESLWNSYFLASILRYTISLNISWLVNSAAHMYGNRPYDKHISPRQNPLVALGAIGEGFHNYHHTFPFDYSASEFGLNFNPTTWFIDFNCWLGLATDRKRATKPMIEARKARTGDSSA

[0165] The full amino acid sequence of the protein of the invention wasfound to have 203 of 284 amino acid residues (71%) identical to, and 242of 284 amino acid residues (85%) similar to, the 357 amino acid residueptnr:SPTREMBL-ACC:Q9YGM2 protein from Gallus gallus (Chicken) (ACYL-COADESATURASE 1 (EC 1.14.99.5) (STEAROYL-COA DESATURASE 1) (FATTY ACIDDESATURASE 1).

[0166] In a further search of public sequence databases, NOV10 was foundto have homology to the amino acid sequences shown in the BLASTP datalisted in Table 10C. TABLE 10C BLASTP results for NOV10 Posi- GeneIndex/ Length Identity tives Identifier Protein/Organism (aa) (%) (%)Expect ptnr:REMTREMBL- SEQUENCE 1 FROM PATENT 330 330/330 330/3301.8e-183 ACC:CAC88580 W00166758 - (100%) (100%) Homo sapiensptnr:SPTRENBL- ACYL-COA DESATURASE (EC 357 203/284 242/284 2.7e-116ACC:Q9YGM2 1.14.99.5) (STEAROYL- (71%) (85%) COA DESATURASE) (FATTY ACIDDESATURASE) (DELTA(9) -DESATURASE) - Gallus gallus ptnr:SPTREMBL-ACYL-COA DESATURASE (EC 324 200/285 236/285 1.7e-114 ACC:Q9PW151.14.99.5) (STEAROYL- (70%) (82%) COA DESATURASE) (FATTY ACIDDESATURASE) (DELTA(9) -DESATURASE) - Ctenopharyngodon idellaptnr:SPTREMBL- ACYL-COA DESATURASE (EC 327 200/286 234/286 2.0e-113ACC:Q92038 1.14.99.5) (STEAROYL- (69%) (81%) COA DESATURASE) (FATTY ACIDDESATURASE) (DELTA(9) -DESATURASE) - Cyprinus carpio ptnr:SPTREMBL-ACYL-COA DESATURASE (EC 324 201/285 230/285 6.7e-113 ACC:Q9PU861.14.99.5) (STEAROYL- (70%) (80%) COA DESATURASE) (FATTY ACIDDESATURASE) (DELTA(9) -DESATURASE) - Cyprinus carpio

[0167] The homology of these sequences is shown graphically in theClustalW analysis shown in Table 10D. The NOV10 polypeptide is providedin lane 1.

[0168] BLAST analysis was performed on sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 10E. TABLE 10E Patp BLASTP Analysis for NOV10 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organisn(aa) (%) (%) E value patp:AAG63225 Amino acid sequence of 330 330/330330/330 1.4e-183 a human lipid (100%) (100%) metabolism enzyme - Homosapiens patp:AAG63850 Amino acid sequence of 330 330/330 330/3301.4e-183 human fatty acid (100%) (100%) desaturase 25934 - Homo sapienspatp:AAG63934 Amino acid sequence of 330 330/330 330/330 1.4e-183 humanfatty acid (100%) (100%) desaturase 25934 - Homo sapiens patp:AAY69378Amino acid sequence of 359 187/284 234/284 2.1e-107 human skin stearoyl-(65%) (82%) CoA desaturase - Homo sapiens patp:AAR25853 MSH-dependentprotein 354 181/284 233/284 3.Ee-105 obtd. from hamster (63%) (82%)flank organ - Mesocricetus auratus

[0169] Table 10I lists domain descriptions from pfam analysis for NOV10.This indicates that the NOV10 sequence has properties similar to thoseof other proteins known to contain these domains and similar to theproperties of these domains. TABLE 10F Domain Analysis of NOV10 Pfamanalysis Model Domain seq-f seq-t hmm-f hmm-t score E-value Desaturase1/1 51 295 . . 1 248 [] 505.3 4.7e−148 Alignments of top-scoringdomains: Desaturase: domain 1 of 1, from 51 to 295: score 505.3, E= 4.7e−148    illgalHlgAlyllallptelkwktvivalllYvitGGlGITaGyHR (SEQ IDNO: 146)    +|+++||||| |  + |++ +|  | ++|+++  + + ||+|||+|| NOV10 51   VLMSLLHLGAVYS-LVLIPKAXPLTLLWAYFCFLLAA-LGVTAGAHR 95LwsHRSYkaklpLrifLaifgtlAvQgsiyeWardHRaHHkysDTdaDPH|||||||+|||||||||| ++++|+|++|+||+||||||||||+|||||| 96LWSHRSYRAKLPLRIFLAVANSMAFQNDIFEWSRDHRAHHKYSETDADPH 145danRGFffSHvGWlLvkkhPavkekgkkldlsDLkaDpVvrFqhryYipl+|+|||||||+||| |+||++|+|||+|||++||+|||||| |++||++ 146NARRGFFFSHIGWLFVRKHRDVIEKGRKLDVTDLLADPVVRIQRKYYKIS 195mvlmgfiLPtLvpgylwGetfwggfvwagflRlvfvlhaTWcVNSaAHkf+|||+|++|||||+| |||++|++++ |++||+++ |+  |+||||||++ 196VVLMCFVVPTLVPWYIWGESLWNSYFLASILRYTISLNISWLVNSAAHMY 245GyrPyDsritPrnnwlvAlvtfGEGwHNfHHtFPyDYRnaekwkweyDlT|+||||++|+||+| ||||+++|||+||+|||||+|| ++|++   +++| 246GNRPYDKHISPRQNPLVALGAIGEGFHNYHHTFPFDYSASEFG-LNFNPT 294 k<-* + 295 T 295

[0170] The ACYL-COA DESATURASE disclosed in this invention is expressedin at least the following tissues: Brain, adrenal gland, eye, retina,colon, ovary, testis. The nucleic acids and proteins of the inventionare useful in potential diagnostic and therapeutic applicationsimplicated in various diseases and disorders described below and/orother pathologies. For example, the compositions of the presentinvention will have efficacy for treatment of patients suffering from:Endometriosis, Fertility, Von Hippel-Lindau (VHL) syndrome, Alzheimer'sdisease, Stroke, Tuberous sclerosis, hypercalceimia, Parkinson'sdisease, Huntington's disease, Cerebral palsy, Epilepsy, Lesch-Nyhansyndrome, Multiple sclerosis, Ataxia-telangiectasia, Leukodystrophies,Behavioral disorders, Addiction, Anxiety, Pain, Neuroprotection,Diabetes and other diseases, disorders and conditions of the like.

[0171] (OMIM 604031) Stearoyl-CoA desaturase (SCD; EC 1.14.99.5) is aniron-containing enzyme that catalyzes a rate-limiting step in thesynthesis of unsaturated fatty acids. The principal product of SCD isoleic acid, which is formed by desaturation of stearic acid. The ratioof stearic acid to oleic acid has been implicated in the regulation ofcell growth and differentiation through effects on cell-membranefluidity and signal transduction. By RT-PCR of adipose tissue RNA withprimers based on the sequence of rat SCD, a partial human SCD cDNA wasisolated. Using RNase protection assays, it was recently found thathuman SCD was expressed at higher levels in colon and esophagealcarcinomas than in the counterpart normal tissues. Additional cDNAscorresponding to the full-length human SCD transcript were clonedleading to 6 predicted amino acid changes. It was recently reported thatthe deduced 359-amino acid SCD protein contains the 3 highly conservedhistidine-containing regions that are essential for the enzyme'scatalytic activity. The coding region of human SCD shares 85% and 82%nucleotide identity with those of mouse Scd1 and Scd2, respectively.Northern blot analysis revealed that SCD is expressed ubiquitously as3.9- and 5.2-kb mRNAs, with the highest levels in brain and liver. The 2transcripts arise from use of alternative polyadenylation signals. Itwas demonstrated that the human SCD gene spans approximately 24 kb andcontains 6 exons. They noted that the organization of the human, mouse,and rat SCD genes is very similar. By analysis of a somatic cell hybridpanel, the SCD gene was mapped to chromosome 10 and a transcriptionallyinactive, processed SCD pseudogene to chromosome 17. Deletions wereidentified in the Scd1 gene in the asebia (ab) mutant mouse, which hasrudimentary sebaceous glands and develops alopecia. Fatty aciddesaturases (EC 1.14.99.-) are enzymes that catalyze the insertion of adouble bond at the delta position of fatty acids.

[0172] There are two distinct families of fatty acid desaturases whichdo not seem to be evolutionary related. Family 1 is composed of:Stearoyl-CoA desaturase (SCD) (EC 1.14.99.5). SCD is a key regulatoryenzyme of unsaturated fatty acid biosynthesis. SCD introduces a cisdouble bond at the delta(9) position of fatty acyl-CoA's such aspalmitoleoyl- and oleoyl-CoA. SCD is a membrane-bound enzyme that isthought to function as a part of a multienzyme complex in theendoplasmic reticulum of vertebrates and fungi. Family 2 is composed of:Plants stearoyl-acyl-carrier-protein desaturase (EC 1.14.99.6), theseenzymes catalyze the introduction of a double bond at the delta(9)position of steraoyl-ACP to produce oleoyl-ACP. This enzyme isresponsible for the conversion of saturated fatty acids to unsaturatedfatty acids in the synthesis of vegetable oils. Cyanobacteria desA anenzyme that can introduce a second cis double bond at the delta positionof fatty acid bound to membranes glycerolipids. DesA is involved inchilling tolerance; the phase transition temperature of lipids ofcellular membranes being dependent on the degree of unsaturation offatty acids of the membrane lipids.

[0173] NOV11

[0174] A disclosed NOV11 nucleic acid of 1411 nucleotides (also referredto as CG50281-01) (SEQ ID NO:21) encoding a novel WNT-10B PROTEINPRECURSOR-like protein is shown in Table 11A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 254-256and ending with a TGA codon at nucleotides 1280-1282. Putativeuntranslated regions upstream from the initiation codon and downstreamfrom the termination codon are underlined and the start and stop codonsare in bold in Table 11A. TABLE 11A NOV11 nucleotide sequence (SEQ IDNO:21) CAAGTGTTTGTGAGTCTGTGTGTCTGAGTTTGCAAGTGAGTGTGTGTCTGTGTGCCGGGCGTTGTGTCTGATTGGGCAAGGTTCCAGGGGTGCTCGCTTGAGTCCTGAGCTGGGACAACGCCTTGACTCTTCTTCTTTAAGACCTCCAAGCCTCAGGGACTCTGGGAATCAAGGGGTGTTTCTTCTTGTTTTGTTTGAGGAGGAATGAGAAGGGTCCTGATCGATCTGCCCACCGGAGCCTCCGGGCTTC GACATGCTGGAGGAGCCCCGGCCGCGGCCTCCGCCCTCGGGCCTCGCGGGTCTCCTGTTCCTGGCGTTGTGCAGTCGGGCTCTAAGCAATGAGATTCTGGGCCTGAAGTTGCCTGGCGAGCCGCCGCTGACGGCCAACACCGTGTGCTTGACGCTGTCCGGCCTGAGCAAGCCGCAGCTAGGCCTGTGCCTGCGCAACCCCGACGTCACGGCGTCCGCGCTTCAGGGTCTGCACATCGCGGTCCACGAGTGTCAGCACCAGCTGCGCGACCAGCGCTGGAACTGCTCCGCGCTTGAGGGCGGCGGCCGCCTGCCGCACCACAGCGCCATCCTCAAGCGCGGTTTCCGAGAAAGTGCTTTTTCCTTCTCCATGCTGGCTGCTGGGGTCATGCACGCAGTAGCCACGGCCTGCAGCCTGGGCAAGCTGGTGAGCTGTGGCTGTGGCTGGAAGGGCAGTGGTGAGCAGGATCGGCTGAGGGCCAAACTGCTGCAGCTGCAGGCACTGTCCCGAGGGAAGGCTCCCCGGGACATCCAGGCACGAATGCGAATCCACAACAACAGGGTGGGGCGCCAGGTGGTAACTGAAAACCTGAAGCGGAAATGCAAGTGTCATGGCACATCAGGCAGCTGCCAGTTCAAGACATGCTGGAGGGCGGCCCCAGAGTTCCGGGCAGTGGGGGCGGCGTTGAGGGAGCGGGTGGGCCGGGCCATCTTCATTGATACCCACAACCGCAATTCTGGAGCCTTCCAGCCCCGTCTGCGTCCCCGTCGCCTCTCAGGAGAGCTGGTCTACTTTGAGAAGTCTCCTGACTTCTGTGAGCGAGACCCCACTATGGGCTCCCCAGGGACAAGGGGCCGGGCCTGCAACAAGACCAGCCGCCTGTTGGATGGCTGTGGCAGCCTGTGCTGTGGCCGTGGGCACAACGTGCTCCGGCAGACACGAGTTGAGCGCTGCCATTGCCGCTTCCACTGGTGCTGCTATGTGCTGTGTGATGAGTGCAAGGTTACAGAGTGGGTGAATGTGTGTAAGTGA GGGTCAACCTTACCTTGGGGCTGGGGAAAAGGACTGTGTGAAAGGAAGCGCCTTTTCAACCCTTTGCTATGATTTCCTTCCAAGGTCACTCTTGGCCCCTGGAAGCTTAAAGATCTAC CTGGAAAAAAC

[0175] The WNT-10B PROTEIN PRECURSOR-like NOV11 disclosed in thisinvention maps to chromosome 12.

[0176] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 641 of 654 bases(98%) identical to a gb:GENBANK-ID:HSU81787|acc:U81787.1 mRNA from Homosapiens (Human Wnt10B mRNA, complete cds).

[0177] A disclosed NOV11 polypeptide (SEQ ID NO:22) encoded by SEQ IDNO:21 has 342 amino acid residues and is presented in Table 11B usingthe one-letter code. NOV11 polypeptides are likely Type Ib (Nexo Ccyt)membrane proteins. Analysis of NOV11 with INTEGRAL software predicts alikelihood of −3.88 of having a transmembrane domain at residues 157-173(156-174). The SignalP, Psort and/or Hydropathy results predict thatNOV11 has a signal peptide and is likely to be localized extracellularlywith a certainty of 0.3700. In an alternative embodiment, NOV11 islikely to be localized to the lysosome (lumen) with a certainty of0.1900, or to the endoplasmic reticulum (membrane) with a certainty of0.1000, or to the endoplasmic reticulum (lumen) with a certainty of0.1000. The most likely cleavage site for a NOV11 signal peptide isbetween amino acids 28 and 29, i.e., at the dash in the sequence ALS-NE.TABLE 11B NOV11 protein sequence (SEQ ID NO:22)MLEEPRPRPPPSGLAGLLFLALCSRALSNEILGLKLPGEPPLTANTVCLTLSGLSKRQLGLCLRNPDVTASALQGLHIAVHECQHQLRDQRWNCSALEGGGRLPHHSAILKRGFRESAFSFSMLAAGVMHAVATACSLGKLVSCGCGWKGSGEQDRLRAKLLQLQALSRGKAPRDIQARMRIHNNRVGRQVVTENLKRKCKCHGTSGSCQFKTCWRAAPEFRAVGAALRERVGRAIFIDTHNRNSGAFQPRLRPRRLSGELVYFEKSPDFCERDPTMGSPGTRGRACNKTSRLLDGCGSLCCGRGHNVLRQTRVERCNCRFHWCCYVLCDECKVTEWVNVCK

[0178] The full amino acid sequence of the protein of the invention wasfound to have 171 of 176 amino acid residues (97%) identical to, and 173of 176 amino acid residues (98%) similar to, the 389 amino acid residueptnr:SWISSPROT-ACC:O00744 protein from Homo sapiens (Human) (WNT-10BPROTEIN PRECURSOR (WNT-12)).

[0179] In a search of public sequence databases, NOV11 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 11C. TABLE 11C BLASTP results for NOV11 Posi- Gene Index/ LengthIdentity tives Identifier Protein/Organism (aa) (%) (%) Expectptnr:TRENBLNEW- WNT10B - Homo sapiens 389 171/176 173/176 4.5e-189ACC:BAB72181 (97%) (98%) ptnr:SWISSPROT- WNT-10B protein 389 171/176173/176 2.5e-188 ACC:000744 precursor (WNT-12) - (97%) (98%) Homosapiens ptnr:SWISSPROT- WNT-10B protein 389 168/176 172/176 9.8e-185ACC:P48614 precursor (WNT-12) - (95%) (97%) Mus musculus ptnr:SPTREMBL-WNT10B - Fugu 390 123/208 154/208 2.5e-119 ACC:P79753 rubripes (Japanese(59%) (74%) pufferfish) (Takifugu rubripes) ptnr:SWISSPROT- WNT-10Aprotein 417 119/182 136/182 2.0e-117 ACC:P70701 precursor - (65%) (74%)Mus musculus

[0180] A multiple sequence alignment is shown in Table 11D, with theprotein of the invention being shown on the first line in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 11C.

[0181] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 11E. TABLE 11E Patp BLASTP Analysis for NOV11 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAW08928 Wnt-10b protein - 389 171/176 173/1764.6e-187 Homo sapiens (97%) (98%) patp:AAR53689 HR2 polypeptide - 389168/176 172/176 7.6e-185 Homo sapiens (95%) (97%) patp:AAY94319 MurineWnt-10A protein - 417 119/182 136/182 1.6e-117 Mus musculus (65%) (74%)patp:AAY28559 Wnt-10a polypeptide #1 - 417 119/182 137/182 4.1e-117 Homosapiens (65%) (75%) patp:AAB95835 Human protein sequence 417 119/182137/182 2.3e-116 SEQ ID NO:18862 - (65%) (75%) Homo sapiens

[0182] Table 11F lists the domain description from DOMAIN analysisresults against NOV11. TABLE 11F Domain Analysis of NOV11 Pfam analysisModel Domain seq-f seq-t hmm-f hmm-t score E-value wnt 1/2 47 161 .. 1115 [. 133.3 4.1e−48 Metallothio_2 1/1 142 214 .. 1  85 [] −33.6 7.4 wnt2/2 174 342 .] 160 352 .] 292.7 4.5e−106 Alignments of top-scoringdomains: wnt: domain 1 of 2, from 47 to 161: score 133.3, E = 4.1e−48lCrslPGLsprQrqlCrrnpdvmasvseGaqlaiqECQhQFRgrRWN (SEQ ID NO:152)+| +| |||+||+ || |||||+||  +|+++|++||||| |  ||| NOV11 47VCLTLSGLSKRQLCLCLRNPDVTASALQGLHIAVHECQHQLRDQRWN 93CStldslnersvfgkvlkkgtREtAFVyAIsSAGVahaVTRaCseGeles||+|++    +  + +||+|+||+|| ++  +|||+|||+ ||| |+| | 94CSALEGGGRLPEHSAILKRGFRESAFSFSMLAAGVMHAVATACSLGKLVS 143CGCDdkRkadeerlrikL<-* |||+ |  +++||| || 144 CGCGWKGSGEQDRLRAKL 161Metallothio_2: domain 1 of 1, from 142 to 214: score −33.6, E = 7.4MSCsCGGnCGCGSgCkCGsGCgGCkmYpdlsettssttteatTlvlG (SEQ ID NO:153)||+|| +   ||| +   + + +     ||      +        + NOV11 142VSCGCGWK---GSGEQDRLRAK-LLQLQALSRGK---APR------D 175VApekkaqfegsEmgvavaaeenGCKC.GsnCkCdPCNC<-*  + +  + +  +  |+++     |||+|++  |   +| 176IQARMRIHNNRVGRQVVTENLKRKCKChGTSGSCQFKTC 214 wnt: domain 2 of 2, from 174to 342: score 292.7, E =4.5e−106rdrdaRsLMNLHNNEAGRkaVkshmrreCKCHGvSGSCslKTCWlsL (SEQ ID NO:154)||  + ++|++|||++||++| ++++|+|||||+||||+ ||||++ NOV11 174RD--IQARMRIHNNRVGRQVVTENLKRKCKCHGTSGSCQFKTCWRAA 218PdFReVGdlLKeKYdgAieVevnkrgkgqrslssrkqasaleaanerfkk|+||+||++|+|+   || +  ++|++|           |+ ++ + ++ 219PEFRAVGAALRERVGRAIFIDTHNRNSG-----------AFQPRLRPRR- 256PtrnQYTDLVYlEkSPDYCerdretGslGTqGRvCnktSkGlqWRDgCel       +|||+|||||+||||+  ||+||+||+|||||+ |   |||++ 257-LSG---ELVYFEKSPDFCERDPTMGSPGTRGRACNKTSRLL---DGCGS 299LCCGRGYnteqKvertekCnCkFHNGWCCyVkCeeCtevvevhtCK<-*||||||+|++  ++|+|+|+|+||  ||||| |+||+ +++| +|| 300LCCGRGHNVLR-QTRVERCHCRFH--WCCYVLCDECKVTEWVNVCK 342

[0183] The WNT-10B PROTEIN PRECURSOR-Like protein disclosed in thisinvention is expressed in at least the following tissues: Melanocytes,heart, uterus, brain, lung, testis, b-cell, ovary. This information wasderived by determining the tissue sources of the sequences that wereincluded in the invention including but not limited to SeqCallingsources, Public EST sources, Literature sources, and/or RACE sources.

[0184] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from: neurodegenerative disorders,epilepsy, cancers including but not limited to brain tumor, colon cancerand breast cancer, developmental disorders, and neural tube defects andother diseases, disorders and conditions of the like.

[0185] WNT genes encode intercellular signaling glycoproteins that playimportant roles in key processes of embryonic development such asmesoderm induction, specification of the embryonic axis, and patterningof the central nervous system, spinal cord, and limbs. The name WNTdenotes the relationship of this family to the Drosophila segmentpolarity gene ‘wingless,’ and to its vertebrate ortholog Int1, a mouseprotooncogene. It was noted that multiple WNT genes are known to existin several species that have been investigated ranging from Drosophilato man. They have been classified into various groups and subgroups onthe basis of high sequence homology and common expression patterns.

[0186] The vertebrate WNT8 subfamily includes genes from Xenopus,zebrafish, and chicken; the first mammalian WNT8 homolog, a human memberof the Wnt8 family that they termed WNT8B was characterized on the basisof the very high sequence similarity (90-91% identity) of the inferredprotein to those encoded by the Xenopus and zebrafish Wnt8b genes. Thehuman cDNA encodes a 295-amino acid polypeptide that contains a C2H2zinc finger-like motif. A predominant 1.9-kb mRNA was detected in avariety of adult and fetal tissues. They used PCR typing of a humanmonochromosomal hybrid cell panel to map the gene to chromosome 10, andfluorescence in situ hybridization for localization at 10q24. Recently,the full-length cDNA sequence and genomic organization of the humanWNT8B gene was reported along with studies of expression of the gene inhuman and mouse embryos. The WNT8B gene contains 6 exons separated bysmall introns, with the exception of intron 1. The predicted protein has351 amino acids. The gene is expressed predominantly as a transcript ofapproximately 2.1 kb. The human and mouse expression patterns appearedto be identical and were restricted to the developing brain, with thegreat majority of expression being found in the developing forebrain. Inthe latter case, expression was confined to the germinativeneuroepithelium of 3 sharply delimited regions: the dorsomedial wall ofthe telencephalic ventricles (which includes the developinghippocampus), a discrete region of the dorsal thalamus, and themammillary and retromammillary regions of the posterior hypothalamus.Expression in the developing hippocampus may suggest a role for WNT8B inpatterning of this region, and subchromosomal localization of the humangene to 10q24 may suggest it as a candidate gene for partial epilepsy(EPT; OMIM-600512) in families in which the disease has been linked tomarkers in this region. WNT1 (OMIM-164820) is a member of a family ofcysteine-rich, glycosylated signaling proteins that mediate diversedevelopmental processes such as the control of cell proliferation,adhesion, cell polarity, and the establishment of cell fates.

[0187] Wnt1 was identified as an oncogene activated by the insertion ofmouse mammary tumor virus in virus-induced mammary adenocarcinomas.Although Wnt1 is not expressed in the normal mammary gland, expressionof Wnt1 in transgenic mice causes mammary tumors. To identify downstreamgenes in the WNT signaling pathway that are relevant to the transformedcell phenotype, a PCR-based cDNA subtraction strategy and suppressionsubtractive hybridization was used. Two genes, WISP1 and WISP2(OMIM-603399), were identified that are upregulated in the mouse mammaryepithelial cell line transformed by Wnt1, but not by Wnt4 (OMIM-603490).Together with a third related gene, WISP3 (OMIM-603399), these proteinsdefine a subfamily of the connective tissue growth factor family. Twodistinct systems demonstrated WISP induction to be associated with theexpression of WNT1. WISP1 genomic DNA was amplified in colon cancer celllines and in human colon tumors and its RNA overexpressed in 84% of thetumors examined compared with patient-matched normal mucosa. WISP3 alsowas overexpressed in 63% of colon tumors analyzed. In contrast, WISP2showed reduced RNA expression in 79% of the tumors. These resultssuggested that WISP genes may be downstream of WNT1 signaling and thataberrant levels of WISP expression in colon cancer may play a role incolon tumorigenesis. It was found that the WISP1 cDNA encodes a367-amino acid protein. Mouse and human WISP1 proteins are 84%identical; both have hydrophobic N-terminal signal sequences, 38conserved cysteine residues, and 4 potential N-linked glycosylationsites. Alignment of the 3 human WISP proteins showed that WISP1 andWISP3 are most similar (42%), whereas WISP2 had 37% identity with WISP1and 32% identity with WISP3.

[0188] Several members of the Wnt gene family have been shown to causemammary tumors in mice. Using degenerate primer PCR on human genomic DNAand specific PCR of cDNA libraries, a Wnt gene was isolated that had notpreviously been described in human. It is the human homolog of mouseWnt10b, which had been shown to be one of the oncogenes cooperating withFGF3 in the development of mouse mammary tumor virus (MMTV)-inducedmammary carcinomas in mice. The human WNT10B sequence is 88 and 95%identical to the murine gene at nucleotide and amino acid levels,respectively. By YAC and fluorescence in situ hybridization (FISH)mapping, the gene was localized to 12q13, a chromosomal regionfrequently rearranged in human tumors and also containing the WNT1 gene.WNT10B expression was not observed in normal and benign proliferationsof human breast tissue but was found to be elevated in 3 of 50 primarybreast carcinomas. Southern blot analysis of the carcinoma expressingthe highest level of WNT10B showed no amplification or rearrangement ofthe gene. It was recently demonstrated that the WNT10B gene encodes a389-amino acid protein with 96.6% sequence identity to mouse Wnt10b. Theexpression pattern showed that it is synthesized in many adult tissueswith the highest levels found in heart and skeletal muscle. By PCRtyping of a human/rodent monochromosomal panel and FISH, they mappedWNT10B to 12q13.1. It was recently shown that WN signaling, likelymediated by WNT10B, is a molecular switch that governs adipogenesis. WNTsignaling maintains preadipocytes in an undifferentiated state throughinhibition of the adipogenic transcription factors CEBPA and PPAR-gamma.When WNT signaling in preadipocytes is prevented by overexpression ofaxin or dominant-negative TCF4, these cells differentiate intoadipocytes. Disruption of WNT signaling also causes transdifferentiationof myoblasts into adipocytes in vitro, highlighting the importance ofthis pathway not only in adipocyte differentiation but also inmesodermal cell fate determination.

[0189] NOV12

[0190] NOV12 includes two novel Kilon Protein Precursor-like proteinsdisclosed below. The disclosed sequences have been named NOV12a andNOV12b. Unless specifically addressed as NOV12a or NOV12b, any referenceto NOV12 is assumed to encompass all variants.

[0191] NOV12a

[0192] A disclosed NOV12a nucleic acid of 11196 nucleotides (alsoreferred to as CG55920-01) (SEQ ID NO:23) encoding a novel Kilon ProteinPrecursor-like protein is shown in Table 12A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 94-96and ending with a TAA codon at nucleotides 1156-1158. Putativeuntranslated regions upstream from the initiation codon and downstreamfrom the termination codon are underlined and the start and stop codonsare in bold in Table 12A. TABLE 12A NOV12a nucleotide sequence (SEQ IDNO:23) GCGCGCCGCCTGGTTCCCGGGAAGACTCGCCAGCACCAGGGGGTGGGGGAGTGCGAGCTGAAAGCTGCTGGAGAGTGAGCAGCCCTAGCAGGG ATGGACATGATGCTGTTGGTGCAGGGTGCTTGTTGCTCGAACCAGTGGCTGGCGGCGGTGCTCCTCAGCCTGTGCTGCCTGCTACCCTCCTGCCTCCCGGCTGGACAGAGTGTGGACTTCCCCTGGGCGGCCGTGGACAACATGATGGTCAGAAAAGGGGACACGGCGGTGCTTAGGTGTTATTTGGAAGATGGAGCTTCAAAGGGTGCCTGGCTGAACCGGTCAAGTATTATTTTTGCGGGAGGTGATAAGTGGTCAGTGGATCCTCGAGTTTCAATTTCAACATTGAATAAAAGGGACTACAGCCTCCAGATACAGAATGTAGATGTGACAGATGATGGCCCATACACGTGTTCTGTTCAGACTCAACATACACCCAGAACAATGCAGGTGCATCTAACTGTGCAAGTTCCTCCTAAGATATATGACATCTCAAATGATATGACCGTCAATGAAGGAACCAACGTCACTCTTACTTGTTTGGCCACTGGGAAACCAGAGCCTTCCATTTCTTGGCGACACATCTCCCCATCAGCAAAACCATTTGAAAATGGACAATATTTGGACATTTATGGAATTACAAGGGACCAGGCTGGGGAATATGAATGCAGTGCGGAAAATGATGTGTCATTCCCAGATGTGAGGAAAGTAAAAGTTGTTGTCAACTTTGCTCCTACTATTCAGGAAATTAAATCTGGCACCGTGACCCCCGGACGCAGTGGCCTGATAAGATGTGAAGGTGCAGGTGTGCCGCCTCCAGCCTTTGAATGGTACAAAGGAGAGAAGAAGCTCTTCAATGGCCAACAAGGAATTATTATTCAAAATTTTAGCACAAGATCCATTCTCACTGTTACCAACGTGACACAGGAGCACTTCGGCAATTATACTTGTGTGGCTGCCAACAAGCTAGGCACAACCAATGCGAGCCTGCCTCTTAACCCTCCAAGTACAGCCCAGTATGGAATTACCGGGAGCGCTGATGTTCTTTTCTCCTGCTGGTACCTTGTGTTGACACTGTCCTCTTTCACCAGCATATTCTACCTGAAGAATGCCATTCTACAATAA ATTCAAAGACCCATAAAAGGCTTTTAAGGATTCTCTGA

[0193] The KILON PROTEIN PRECURSOR-like NOV12a disclosed in thisinvention maps to chromosome 1.

[0194] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 1003 of 1167 bases(85%) identical to a gb:GENBANK-ID:AB017139|acc:AB017139.1 mRNA fromRattus norvegicus (Rattus norvegicus mRNA for Kilon, complete cds).

[0195] A disclosed NOV12a polypeptide (SEQ ID NO:24) encoded by SEQ IDNO:23 has 354 amino acid residues and is presented in Table 12B usingthe one-letter code. The Psort and Hydropathy results predict that thissequence has a signal peptide and is likely to be localizedextracellularly with a certainty of 0.8200. In an alternativeembodiment, NOV12a is likely to be localized to the lysosome (lumen)with a certainty of 0.5088, or to the endoplasmic reticulum (membrane)with a certainty of 0.1000, or to the endoplasmic reticulum (lumen) witha certainty of 0.1000. Most likely cleavage site for a NOV12a signalpeptide is between pos. 33 and 34, i.e., at the dash in the sequenceCLP-AG. TABLE 12B NOV12a protein sequence (SEQ ID NO:24)MDMMLLVQGACCSNQWLAAVLLSLCCLLPSCLPAGQSVDFPWAAVDNMMVRKGDTAVLRCYLEDGASKGAWLNRSSIIFAGGDKWSVDPRVSISTLNKRDYSLQIQNVDVTDDGPYTCSVQTQHTPRTMQVHLTVQVPPKIYDISNDMTVNEGTNVTLTCLATGKPEPSISWRHISPSAKPFENGQYLDIYGITRDQAGEYECSAENDVSFPDVRKVKVVVNFAPTIQEIKSGTVTPGRSGLIRCEGAGVPPPAFEWYKGEKKLFNGQQGIIIQNFSTRSILTVTNVTQEHFGNYTCVAANKLGTTNASLPLNPPSTAQYGITGSADVLFSCWYLVLTLSSFTSIFYLKN AILQ

[0196] The full amino acid sequence of the protein of the invention wasfound to have 334 of 352 amino acid residues (94%) identical to, and 341of 352 amino acid residues (96%) similar to, the 348 amino acid residueptnr:SWISSPROT-ACC:Q9Z0J8 protein from Rattus norvegicus (Rat) (KILONPROTEIN PRECURSOR (KINDRED OF IGLON)).

[0197] The NOV12a disclosed in this invention is expressed in at leastthe following tissues: brain. The nucleic acids and proteins of theinvention are useful in potential diagnostic and therapeuticapplications implicated in various diseases and disorders describedbelow and/or other pathologies. For example, the compositions of thepresent invention will have efficacy for treatment of patients sufferingfrom: Von Hippel-Lindau (VHL) syndrome, Alzheimer's disease, Stroke,Tuberous sclerosis, hypercalceimia, Parkinson's disease, Huntington'sdisease, Cerebral palsy, Epilepsy, Lesch-Nyhan syndrome, Multiplesclerosis, Ataxia-telangiectasia, Leukodystrophies, Behavioraldisorders, Addiction, Anxiety, Pain, Neuroprotection and other diseases,disorders and conditions of the like.

[0198] NOV12b

[0199] A disclosed NOV12b nucleic acid of 1165 nucleotides (alsoreferred to as CG55920-04) (SEQ ID NO:25) encoding a novel Kilon ProteinPrecursor-like protein is shown in Table 12C. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 77-79and ending with a TAA codon at nucleotides 1139-1141. Putativeuntranslated regions upstream from the initiation codon and downstreamfrom the termination codon are underlined and the start and stop codonsare in bold in Table 12C. TABLE 12C NOV12b nucleotide sequence (SEQ IDNO:25) CGGGAAGACTCGCCAGCACCTGGGGGTGGGGGAGTGCGAGCTGAAAGCTGCTGGAGAGTGAGCAGCCCTAGCAGGG ATGGACATGATGCTGTTGGTGCAGAGTGCCTGTTGCTCGAACCAGCGGCTGGCGGCGGTGCTTCTCAGCCTGTGCTGCCTGCTACCCTCCTGCCTCCCGGCTGGACAGAGTGTGGACTTCCCCTGGGCGGCCGTGGACAACATGATGGTCAGAAAAGGGGACACGGCGGTGCTTAGGTGTTATTTGGAAGATGGAGCTTCAAAGGGTGCCTGGCTGAACCGGTCAAGTATTATTTTTGCGGGAGGTGATAAGTGGTCAGTGGATCCTCGAGTTTCAATTTCAACATTGAATAAAAGGGACTACAGCCTCCAGATACAGAATGTAGATGTGACAGATGATGGCCCATACACGTGTTCTGTTCAGACTCAACATACACCCAGAACAATGCAGGTGCATCTAACTGTGCAAGTTCCTCCTAAGATATATGACATCTCAAATGATATGACCGTCAATGAAGGAACCAACGTCACTCTTACTTGTTTGGCCACTGGGAAACCAGAGCCTTCCATTTCTTGGCGACACATCTCCCCATCAGCAAAACCATTTGAAAATGGACAATATTTGGACATTTATGGAATTACAAGGGACCAGGCTGGGGAATATGAATGCAGTGCGGAAAATGATGTGTCATTCCCAGATGTGAGGAAAGTAAAAGTTGTTGTCAACTTTGCTCCTACTATTCAGGAAATTAAATCTGGCACCGTGACCCCCGGACGCAGTGGCCTGATAAGATGTGAAGGTGCAGGTGTGCCGCCTCCAGCCTTTGAATGGTACAAAGGAGAGAAGAAGCTCTTCAATGGCCAACAAGGAATTATTATTCAAAATTTTAGCACAAGATCCATTCTCACTGTTACCAACGTGACACAGGAGCACTTCGGCAATTATACTTGTGTGGCTGCCAACAAGCTAGGCACAACCAATGCGAGCCTGCCTCTTAACCCTCCAAGTACAGCCCAGTATGGAATTACCGGGAGCGCTGATGTTCTTTTCTCCTGCTGGTACCTTGTGTTGACACTGTCCTCTTTCACCAGCATATTCTACCTGAAGAATGCCATTCTACAATAA ATTCAAAGA CCCATAAAAGGCTTT

[0200] The KILON PROTEIN PRECURSOR-like NOV12b disclosed in thisinvention maps to chromosome 1.

[0201] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 989 of 1154 bases(85%) identical to a gb:GENBANK-ID:AB017139|acc:AB017139.1 mRNA fromRattus norvegicus (Rattus norvegicus mRNA for Kilon, complete cds).

[0202] A disclosed NOV12b polypeptide (SEQ ID NO:26) encoded by SEQ IDNO:25 has 354 amino acid residues and is presented in Table 12B usingthe one-letter code. NOV12b seems to be a Type II (Ncyt Cexo) membraneprotein with an INTEGRAL Likelihood of −5.41 Transmembrane 17-33(15-36). The Psort and Hydropathy results predict that this sequence hasa signal peptide and is likely to be localized at the Golgi body with acertainty of 0.9000. In an alternative embodiment, NOV12b is likely tobe localized to the mitochondrial inner membrane with a certainty of0.8084, or to the plasma membrane with a certainty of 0.6500, or to themitochondrial intermembrane space with a certainty of 0.4883. Mostlikely cleavage site for a NOV12b signal peptide is between pos. 33 and34, i.e., at the dash in the sequence CLP-AG. TABLE 12D NOV12b proteinsequence (SEQ ID NO:26)MDMMLLVQSACCSNQRLAAVLLSLCCLLPSCLPAGQSVDFPWAAVDNMMVRKGDTAVLRCYLEDGASKGAWLNRSSIIFAGGDKWSVDPRVSISTLNKRDYSLQIQNVDVTDDGPYTCSVQTQHTPRTMQVHLTVQVPPKIYDISNDMTVNEGTNVTLTCLATGKPEPSISWRHISPSAKPFENGQYLDIYGITRDQAGEYECSAENDVSFPDVRKVKVVVNFAPTIQEIKSGTVTPGRSGLIRCEGAGVPPPAFEWYKGEKKLFNGQQGIIIQNFSTRSILTVTNVTQEHFGNYTCVAANKLGTTNASLPLNPPSTAQYGITGSADVLFSCWYLVLTLSSFTSIFYLKN AILQ

[0203] The full amino acid sequence of the protein of the invention wasfound to have 332 of 352 amino acid residues (94%) identical to, and 339of 352 amino acid residues (96%) similar to, the 348 amino acid residueptnr:SWISSPROT-ACC:Q9Z0J8 protein from Rattus norvegicus (Rat) (KILONPROTEIN PRECURSOR (KINDRED OF IGLON)).

[0204] The KILON PROTEIN PRECURSOR-like gene disclosed in this inventionis expressed in at least the following tissues: brain. The nucleic acidsand proteins of the invention have applications in the diagnosis and/ortreatment of various diseases and disorders. For example, thecompositions of the present invention will have efficacy for thetreatment of patients suffering from: Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy,Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia,Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain,Neuroprotection, as well as other diseases, disorders and conditions.

[0205] NOV12a and NOV12b share a high degree of homology as is shown inthe amino acid alignment in Table 12E.

[0206] In a search of public sequence databases, NOV12 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 12F. TABLE 12F BLASTP results for NOV12 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SWISSPROT- Kilon protein precursor 348 334/352 341/352 1.8e-181ACC:Q9Z0J8 (Kindred of IgLON) - (94%) (96%) Rattus norvegicusptnr:SPTREMBL- NEUROTRACTIN-L - 352 290/351 317/351 5.5e-157 ACC:Q9W6V2Gallus gallus (82%) (90%) ptnr:SPTREMBL- NEUROTRACTIN-S - 261 183/226200/226 1.6e-95 ACC:Q9W6V1 Gallus gallus (80%) (88%) ptnr:SWISSPROT-Limbic system-associated 338 186/323 236/323 1.6e-95 ACC:Q13449 membraneprotein (57%) (73%) precursor (LSAMP) - Homo sapiens ptnr:SWISSPROT-Limbic system-associated 338 182/323 236/323 8.8e-95 ACC:Q98919 membraneprotein (56%) (73%) precursor (E19S) (CHLAMP, G19-isoform) - Gallusgallus

[0207] A multiple sequence alignment is shown in Table 120, with theprotein of the invention being shown on the first line in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 12F.

[0208] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 12H. TABLE 12H Patp BLASTP Analysis for NOV12 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAB31212 Amino acid sequence of 354 354/354354/354 7.2e-194 human polypeptide (100%) (100%) PR06004 - Homo sapienspatp:AAB44331 Human PR04993 protein 352 351/352 351/352 7.4e-192sequence SEQ ID NO:612 - (99%) (99%) Homo sapiens patp:AAW05152 HumanLAMP residues 8- 325 186/323 236/323 l.2e-95 332 - Homo sapiens (57%)(73%) patp:AAW05153 Rat LAMP residues 1-332 - 338 185/323 235/3236.8e-95 Rattus rattus (57%) (72%) patp:AAW05154 Rat LAMP residues1-332 - 338 185/323 235/323 6.8e-95 Rattus rattus (57%) (72%)

[0209] Table 12I lists the domain description from DOMAIN analysisresults against NOV12. TABLE 12F Domain Analysis of NOV12 Pfam analysisModel Domain seq-f seq-t hmm-f hmm-t score E-value ig 1/3 53 120 .. 1 45[] 26.5 1.1e−06 ig 2/3 153 205 .. 1 45 [] 28.4   3e−07 ig 3/3 238 299 ..1 45 [] 27.6 5.4e−07 Alignments of top-scoring domains: ig: domain 1 of3, from 53 to 120: score 26.5, E = 1.1e−06GesvtLtCsvsgfgpp.p.vtWlrngk.................... (SEQ ID NO: 160)|+++ |+|+     ++  +  ||  +     ++++ + +++ + ++ NOV12a 53GDTAVLRCYLE---DGaSkGAWLNRSSiifaggdkwsvdprvsistl 96....lslti.svtpeDsgGtYtCvv<-* +++++||+|++|   |+ | ||| | 97nkrdYSLQIqNVDVTDD-GPYTCSV 120 ig: domain 2 of 3, from 153 to 205: score28.4, E = 3e−07 GesvtLtCsvsgfgpp.p.vtWlrngk........lslti.svtpeD (SEQ IDNO:161) |  ||||| ++  | |+|+++|++ +++ ++ +++  | |   |++ NOV12a 153GTNVTLTCLAT--GKPePsISWRHISPsakpfengQYLDIyGITRDQ 197 sgGtYtCvv<-*+ |+| | + 198 A-GEYECSA 205 ig: domain 3 of 3, from 238 to 299: score27.6, E = 5.4e−07 GesvtLtCsvsgfgpp.p.vtWlrngk.................lsl (SEQID NO:162) | |  ++|+    | |+| + |+++ |+  +++++   ++ ++++ | NOV12a 238GRSGLIRCEGA--GVPpPaFEWYKGEKklfngqqgiiiqnfstrSIL 282ti.svtpeDsgGtYtCvv<-* |+++||+|+  |+||||+ 283 TVtNVTQEHF-GNYTCVA 299

[0210] In the central nervous system, many cell adhesion molecules areknown to participate in the establishment and remodeling of the neuralcircuit. Some of the cell adhesion molecules are known to be anchored tothe membrane by the glycosylphosphatidylinositol (GPI) inserted to theirC termini, and many GPI-anchored proteins are known to be localized in aTriton-insoluble membrane fraction of low density or so-called “raft.” Anovel protein was found in this fraction which was an immunoglobulinsuperfamily member with three C2 domains and has six putativeglycosylation sites. Since this protein shows high sequence similarityto IgLON family members including LAMP, OBCAM, neurotrimin, CEPU-1,AvGP50, and GP55, this protein was termed Kilon (a kindred of IgLON).Kilon immunostaining was observed in the cerebral cortex andhippocampus, in which the strongly stained puncta were observed ondendrites and soma of pyramidal neurons.

[0211] The basic structure of immunoglobulin (Ig) molecules is atetramer of two light chains and two heavy chains linked by disulfidebonds. There are two types of light chains: kappa and lambda, eachcomposed of a constant domain (CL) and a variable domain (VL). There arefive types of heavy chains: alpha, delta, epsilon, gamma and mu, allconsisting of a variable domain (VH) and three (in alpha, delta andgamma) or four (in epsilon and mu) constant domains (CH1 to CH4).Members of the immunoglobulin superfamily are found in hundreds ofproteins of different functions. Examples include antibodies, the giantmuscle kinase titin and receptor tyrosine kinases. Immunoglobulin-likedomains may be involved in protein-protein and protein-ligandinteractions.

[0212] NOV13

[0213] NOV13 includes two novel Organic Cation Transporter-like proteinsdisclosed below. The disclosed sequences have been named NOV13a andNOV13b. Unless specifically addressed as NOV13a or NOV13b, any referenceto NOV13 is assumed to encompass all variants.

[0214] NOV13a

[0215] A disclosed NOV13a nucleic acid of 2069 nucleotides (alsoreferred to as CG55988-01) (SEQ ID NO:27) encoding a novel OrganicCation Transporter-like protein is shown in Table 13A. An open readingframe was identified beginning with an ATG initiation codon atnucleotides 279-281 and ending with a TAA codon at nucleotides1881-1883. Putative untranslated regions upstream from the initiationcodon and downstream from the termination codon are underlined and thestart and stop codons are in bold in Table 13A. TABLE 13A NOV13anucleotide sequence (SEQ ID NO:27)GCTTCTAGGCCTTCTCAGTAGATGGAGCTAAGTAATATATGTATATATACTAACCCACAGATATAAATATGTCTATAATTATTTCTATATTTATCCATTCGTGTATATGTTAAGATAAACATGATGGAGACCCTTCAAATTTGCTTATGTTCTTTTTCAGCCTATAGACCAGATATAATAATTAGCTTTTCTTCTCTTGCAGATTCCAGAGAGTCCTCTATTTCATATGTGCCTTCCAGAACATCTCTTGTGGTATTCACTACTTGGCTTCTGTGTTC ATGGGAGTCACCCCTCATCATGTCTGCAGGCCCCCAGGCAATGTGAGTCAGGTTGTTTTCCATAATCACTCTAATTGGAGTTTGGAGGACACCGGGGCCCTGTTGTCTTCAGGCCAGAAAGATTATGTTACGGTGCAGTTGCAGAATGGTGAGATCTGGGAGCTCTCAAGGTGTAGCAGGAATAAGAGGGAGAACACATCGAGTTTGGGCTATGAATACACTGGCAGTAAGAAAGAGTTTCCTTGTGTGGATGGCTACATATATGACCAGAACACATGGAAAAGCACTGCGGTGACCCAGTGGAACCTGGTCTGTGACCGAAAATGGCTTGCAATGCTGATCCAGCCCCTATTTATGTTTGGAGTCCTACTGGGATCGGTGACTTTTGGCTACTTTTCTGACAGGCTAGGACGCCGGGTGGTCTTGTGGGCCACAAGCAGTAGCATGTTTTTGTTTGGAATAGCAGCGGCGTTTGCAGTTGATTATTACACCTTCATGGCTGCTCGCTTTTTTCTTGCCATGGTTGCAAGTGGCTATCTTGTGGTGGGGTTTGTCTATGTGATGGAATTCATTGGCATGAAGTCTCGGACATGGGCGTCTGTCCATTTGCATTCCTTTTTTGCAGTTGGAACCCTGCTGGTGGCTTTGACAGGATACTTGGTCAGGACCTGGTGGCTTTACCAGATGATCCTCTCCACAGTGACTGTCCCCTTTATCCTGTGCTGTTGGGTGCTCCCAGAGACACCTTTTTGGCTTCTCTCAGAGGGACGATATGAAGAAGCACAAAAAATAGTTGACATCATGGCCAAGTGGAACAGGGCAAGCTCCTGTAAACTGTCAGAACTTTTATCACTGGACCTACAAGGTCCTGTTAGTAATAGCCCCACTGAAGTTCAGAAGCACAACCTATCATATCTGTTTTATAACTGGAGCATTACGAAAAGGACACTTACCGTTTGGCTAATCTGGTTCACTGGAAGTTTGGGATTCTACTCGTTTTCCTTGAATTCTGTTAACTTAGGAGGCAATGAATACTTAAACCTCTTCCTCCTGGGTGTAGTGGAAATTCCCGCCTACACCTTCGTGTGCATCGCCATGGACAAGGTCGGGAGGAGAACAGTCCTGGCCTACTCTCTTTTCTGCAGTGCACTGGCCTGTGGTGTCGTTATGGTGATCCCCCAGAAACATTATATTTTGGGTGTGGTGACAGCTATGGTTGGAAAATTTGCCATCGGGGCAGCATTTGGCCTCATTTATCTTTATACAGCTGAGCTGTATCCAACCATTGTAAGATCGCTGGCTGTGGGAAGCGGCAGCATGGTGTGTCGCCTGGCCAGCATCCTGGCGCCGTTCTCTGTGGACCTCAGCAGCATTTGGATCTTCATACCACAGTTGTTTGTTGGGACTATGGCCCTCCTGAGTGGAGTGTTAACACTAAAGCTTCCAGAAACCCTTGGGAAACGGCTAGCAACTACTTGGGAGGAGGCTGCAAAACTGGAGTCAGAGAATGAAAGCAAGTCAAGCAAATTACTTCTCACAACTAATAATAGTGGGCTGGAAAAAACGGAAGCGATTACCCCCAGGGATTCTGGTCTTGGTGAATAA ATGTGCCATGCCTGCTGTCTAGCACCTGAAATATTATTTACCCTAATGCCTTTGTATTAGAGGAATCTTATTCTCATCTCCCATATGTTGTTTGTATGTCTTTTTAATAAATTTTGTAAGAAAATTTTAAAGCAAATATGTTATAAAAGAAATAAAAACTAAGATGA AAATTCTCAGTTTTAAAAA

[0216] The Organic Cation Transporter-like NOV13a disclosed in thisinvention maps to chromosome 6.

[0217] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 411 of 682 bases(60%) identical to a gb:GENBANK-ID:AB015050|acc:AB015050.1 mRNA fromHomo sapiens (Homo sapiens mRNA for OCTN2, complete cds).

[0218] A disclosed NOV13a polypeptide (SEQ ID NO:28) encoded by SEQ IDNO:27 has 534 amino acid residues is presented in Table 13B using theone-letter code. NOV13a is likely a Type IIIa membrane protein (NcytCexo) with an INTEGRAL Likelihood of −5.89 for Transmembrane 229-245(228-246), an INTEGRAL Likelihood of −5.10 for Transmembrane 376-392(373-395), an INTEGRAL Likelihood of −4.57 for Transmembrane 171-187(165-191), an INTEGRAL Likelihood of −4.51 for Transmembrane 348-364(346-366), an INTEGRAL Likelihood of −3.08 for Transmembrane 205-221(205-222), an INTEGRAL Likelihood of −3.03 for Transmembrane 111-127(108-129), an INTEGRAL Likelihood of −2.44 for Transmembrane 398-414(397-415), an INTEGRAL Likelihood of −2.07 for Transmembrane 465-481(465-481), an INTEGRAL Likelihood of −1.12 for Transmembrane 140-156(140-156), and an INTEGRAL Likelihood of −0.59 for Transmembrane 446-462(446-463). The Psort and Hydropathy results predict that NOV13a has asignal peptide and is likely to be localized to the plasma membrane witha certainty of 0.6000. In an alternative embodiment, NOV13a is likely tobe localized to the Golgi body with a certainty of 0.4000, or to theendoplasmic reticulum (membrane) with a certainty of 0.3000, or to themicrobody (peroxisome) with a certainty of 0.3000. TABLE 13B NOV13aprotein sequence (SEQ ID NO:28)MGVTPHHVCRPPGNVSQVVFHNNSNWSLEDTGALLSSGQKDYVTVQLQNGEIWELSRCSRNKRENTSSLGYEYTGSKKEFPCVDGYIYDQNTWKSTAVTQWNLVCDRKWLAMLIQPLFMFGVLLGSVTFGYFSDRLGRRVVLWATSSSMFLFGIAAAFAVDYYTFMAARFFLAMVASGYLVVGFVYVMEFIGMKSRTWASVHLHSFFAVGTLLVALTGYLVRTWWLYQMILSTVTVPFILCCWVLPETPFWLLSEGRYEEAQKIVDIMAKWNRASSCKLSELLSLDLQGPVSNSPTEVQKHNLSYLFYNWSITKRTLTVWLIWFTGSLGFYSFSLNSVNLGGNEYLNLFLLGVVEIPAYTFVCIAMDKVGRRTVLAYSLFCSALACGVVMVIPQKHYILGVVTANVGKFAIGAAFGLIYLYTAELYPTIVRSLAVGSGSMVCRLASILAPFSVDLSSIWIFIPQLFVGTMALLSGVLTLKLPETLGKRLATTWEEAAKLESENESKSSKLLLTTNNSGLEKTEAITPRDSGLGE

[0219] The full amino acid sequence of the protein of the invention wasfound to have 430 of 430 amino acid residues (100%) identical to, and430 of 430 amino acid residues (100%) similar to, the 456 amino acidresidue ptnr:SPTREMBL-ACC:014567 protein from Homo sapiens (Human)(WIGSC:RG331P03.1 PROTEIN).

[0220] The Organic Cation Transporter disclosed in this invention isexpressed in at least the following tissues: Liver, Spleen, germ cell,heart, lung, testis, b-cell. The nucleic acids and proteins of theinvention are useful in potential diagnostic and therapeuticapplications implicated in various diseases and disorders describedbelow and/or other pathologies. For example, the compositions of thepresent invention will have efficacy for treatment of patients sufferingfrom: Cardiomyopathy, Atherosclerosis, Hypertension, Congenital heartdefects, Aortic stenosis, Atrial septal defect (ASD), Atrioventricular(A-V) canal defect, Ductus arteriosus, Pulmonary stenosis, Subaorticstenosis, Ventricular septal defect (VSD), valve diseases, Tuberoussclerosis, Scleroderma, Obesity, Transplantation, Von Hippel-Lindau(VHL) syndrome, Cirrhosis, Hemophilia, Hypercoagulation, Idiopathicthrombocytopenic purpura, Immunodeficiencies, Graft versus host,Fertility, Systemic lupus erythematosus, Autoimmune disease, Asthma,Emphysema, Scleroderma, allergy, ARDS, and other diseases, disorders andconditions of the like.

[0221] NOV13b

[0222] A disclosed NOV13b nucleic acid of 1666 nucleotides (alsoreferred to as CG55988-02) (SEQ ID NO:29) encoding a novel OrganicCation Transporter-like protein is shown in Table 13C. An open readingframe was identified beginning with an ATG initiation codon atnucleotides 76-78 and ending with a TAA codon at nucleotides 1654-1656.Putative untranslated regions upstream from the initiation codon anddownstream from the termination codon are underlined and the start andstop codons are in bold in Table 13C. TABLE 13C NOV13b nucleotidesequence (SEQ ID NO:29)TTCCAGAGAGTCCTCTATTTCATATGTGCCTTCCAGAACATCTCTTGTGGTATTCACTACTTGGCTTCTGTGTTC ATGGGAGTCACCCCTCATCATGTCTGCAGGCCCCCAGGCAATGTGAGTCAGGTTGTTTTCCATAATCACTCTAATTGGAGTTTGGAGGACACCGGGGCCCTGTTGTCTTCAGGCCAGAAAGATTATGTTACGGTGCAGTTGCAGAATGGTGAGATCTGGGAGCTCTCAAGGTGTAGCAGGAATAAGAGGGAGAACACATCGAGTTTGGGCTATGAATACACTGGCAGTAAGAAAGAGTTTCCTTGTGTGGATGGCTACATATATGACCAGAACACATGGAAAAGCACTGCGGTGACCCAGTGGAACCTGGTCTGTGACCGAAAATGGCTTGCAATGCTGATCCAGCCCCTATTTATGTTTGGAGTCCTACTGGGATCGGTGACTTTTGGCTACTTTTCTGACAGGCTTTTTTGCCTATATGTGATTTGCAATGGGGTCAGACTCCTCAATAGTTATAAATGTGACCTTGAATATAAATCCCTATTATTTGTTTTTCAGGTTGCAAGTGGCTATCTTGTGGTGGGGTTTGTCTATGTGATGGAATTCATTGGCATGAAGTCTCGGACATGGGCGTCTGTCCATTTGCATTCCTTTTTTGCAGTTGGAACCCTGCTGGTGGCTTTGACAGGATACTTGGTCAGGACCTGGTGGCTTTACCAGATGATCCTCTCCACAGTGACTGTCCCCTTTATCCTGTGCTGTTGGGTGCTCCCAGAGACACCTTTTTGGCTTCTCTCAGAGGGACGATATGAAGAAGCACAAAAAATAGTTGACATCATGGCCAAGTGGAACAGGGCAAGCTCCTGTAAACTGTCAGAACTTTTATCACTGGACCTACAAGGTCCTGTTAGTAATAGCCCCACTGAAGTTCAGAAGCACAACCTATCATATCTGTTTTATAACTGGAGCATTACGAAAAGGACACTTACCGTTTGGCTAATCTGGTTCACTGGAAGTTTGGGATTCTACTCGTTTTCCTTGAATTCTGTTAACTTAGGAGGCAATGAATACTTAAACCTCTTCCTCACAGGTGTAGTGGAAATTCCCGCCTACACCTTCGTGTGCATCGCCATGGACAAGGTCGGGAGGAGAACAGTCCTGGCCTACTCTCTTTTCTGCAGTGCACTGGCCTGTGGTGTCGTTATGGTGATCCCCCAGGTGAGTTATCTTCTGGGTGTGGTGACAGCTATGGTTGGAAAATTTGCCATCGGGGCAGCATTTGGCCTCATTTATCTTTATACAGCTGAGCTGTATCCAACCATTGTAAGGTCGCTGGCTGTGGGAAGCGGCAGCATGGTGTGTCGCCTGGCCAGCATCCTGGCGCCGTTCTCTGTGGACCTCAGCAGCATTTGGATCTTCATACCACAGTTGTTTGTTGGGACTATGGCCCTCCTGAGTGGAGTGTTAACACTAAAGCTTCCAGAAACCCTTGGGAAACGGCTAGCAACTACTTGGGAGGAGGCTGCAAAACTGGAGTCAGAGAATGAAAGCAAGTCAAGCAAATTACTTCTCACAACTAATAATAGTGGGCTGGAAAAAACGGAAGCGATTACCCCCAGGGATTCTGGTCTTGGT GAATAA ATGTGCCATG

[0223] The Organic Cation Transporter-like NOV13b disclosed in thisinvention maps to chromosome 6.

[0224] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 407 of 682 bases(59%) identical to a gb:GENBANK-ID:AB015050|acc:AB015050.1 mRNA fromHomo sapiens (Homo sapiens mRNA for OCTN2, complete cds).

[0225] A disclosed NOV13b polypeptide (SEQ ID NO:30) encoded by SEQ IDNO:29 has 526 amino acid residues is presented in Table 13D using theone-letter code. NOV13b is likely a Type IIIa membrane protein (NcytCexo) with an INTEGRAL Likelihood of −5.89 for Transmembrane 221-237(220-238), an INTEGRAL Likelihood of −5.10 for Transmembrane 368-384(365-399), an INTEGRAL Likelihood of −4.94 for Transmembrane 161-177(160-180), an INTEGRAL Likelihood of −3.08 for Transmembrane 197-213(197-214), an INTEGRAL Likelihood of −3.03 for Transmembrane 111-127(108-129), an INTEGRAL Likelihood of −2.13 for Transmembrane 340-356(340-358), an INTEGRAL Likelihood of −2.07 for Transmembrane 390-406(389-407), an INTEGRAL Likelihood of −2.07 for Transmembrane 457-473(457-473), and an INTEGRAL Likelihood of −0.59 for Transmembrane 438-454(438-455).

[0226] NOV13b PSORT results suggest that the organic cationtransporter-like protein may be localized at the plasma membrane via aglycosyl phosphtidylinositol anchor typical of type III proteins.However, the protein of CuraGen Acc. No. CG55988-02 predicted here issimilar to the transporter family, all members of which are localized tothe plasma membrane with membrane-spanning segments. This prediction isalso consistent with the results of the hydrophobicity analysis.Therefore it is likely that this novel organic cation transporter-likeprotein is localized to the plasma membrane with a certainty of 0.6000.In an alternative As embodiment, NOV13a is likely to be localized to theGolgi body with a certainty of 0.4000, or to the endoplasmic reticulum(membrane) with a certainty of 0.3000, or to the microbody (peroxisome)with a certainty of 0.3000. TABLE 13D NOV13b protein sequence (SEQ IDNO:30) MGVTPHHVCRPPGNVSQVVFNNHSNWSLEDTGALLSSGQKDYVTVQLQNGEIWELSRCSRNKRENTSSLGYEYTGSKKEFPCVDGYIYDQNTWKSTAVTQWNLVCDRKWLAMLIQPLFMFGVLLGSVTFGYFSDRLFCLYVICNGVRLLNSYKCDLEYKSLLFVFQVASGYLVVGFVYVMEFIGMKSRTWASVHLHSFFAVGTLLVALTGYLVRTWWLYQMILSTVTVPFILCCWVLPETPFWLLSEGRYEEAQKIVDIMAKWNRASSCKLSELLSLDLQGPVSNSFTEVQKHNLSYLFYNWSITKRTLTVWLIWFTGSLGFYSFSLNSVNLGGNEYLNLFLTGVVEIPAYTFVCIAMDKVGRRTVLAYSLFCSALACGVVMVIPQVSYLLGVVTAMVGKFAIGAAFGLIYLYTAELYPTIVRSLAVGSGSMVCRLASILAPFSVDLSSIWIFIPQLFVGTMALLSGVLTLKLPETLGKRLATTWEEAAKLESENESKSSKLLLTTNNSGLEKTEAITPRDSGLGE

[0227] The full amino acid sequence of the protein of the invention wasfound to have 168 of 490 amino acid residues (34%) identical to, and 270of 490 amino acid residues (55%) similar to, the 551 amino acid residueptnr:SPTREMBL-ACC:014546 protein from Homo sapiens (Human) (POLYSPECIFICORAGANIC CATION TRANSPORTER).

[0228] The organic cation transporter-like gene disclosed in thisinvention is expressed in at least the following tissues: bone marrow,lymphoid tissue, testis, pituitary gland, pancreas, brain, liver andspleen. It is also expressed in the following disease conditions:anaplastic astrocytoma, colorectal carcinoma, ovarian serousadenocarcinoma, ovarian cystadenoma, fibrillary astrocytoma,oligodendroglioma, pilocytic astrocytoma, breast cancer. It isupregulated in microvascular endothelial cells in response to vascularendothelial growth factor treatment. Furthermore, the sequence ispredicted to be expressed in the following tissues because of theexpression pattern of (GENBANK-ID:gb:GENBANK-ID:AB015050|acc:AB015050.1) a closely related Homo sapiensmRNA for OCTN2, complete cds homolog in species Homo sapiens: kidney,skeletal muscle, heart, and placenta.

[0229] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: hemophilia,hypercoagulation, idiopathic thrombocytopenic purpura, autoimmunedisease, allergies, immunodeficiencies, transplantation, graft versushost disease (GVHD), lymphaedema, fertility disorders, endocrinedysfunctions, diabetes, obesity, growth and reproductive disorders, VONHippel-Lindau (VHL) syndrome, Alzheimer's disease, stroke, tuberoussclerosis, hypercalceimia, Parkinson's disease, Huntington's disease,cerebral palsy, epilepsy, Lesch-Nyhan syndrome, multiple sclerosis,ataxia-telangiectasia, leukodystrophies, behavioral disorders,addication, anxiety, pain, neurodegeneration, pancreatitis, cirrhosis,cancer, tissue degeneration, bacterial/viral/parasitic infections aswell as other diseases, disorders and conditions.

[0230] NOV13a and NOV13b share a high degree of homology as is shown inthe amino acid alignment in Table 13E.

[0231] In a search of public sequence databases, NOV13 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 13F. TABLE 13F BLASTP results for NOV13 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SPTREMBL- ORGANIC CATION 577 533/534 533/534 7.2e-290 ACC:Q96RU0TRANSPORTER OKB1 - (99%) (99%) Homo sapiens ptnr:SPTREMBL-WUGSC:RG331P03.1 456 430/430 430/430 1.8e-236 ACC:014567 PROTEIN - Homo(100%) (100%) sapiens ptnr:SPTREMBL- CDNA FLJ32744 FIS, 361 353/354353/354 2.4e-188 ACC:Q96M90 CLONE TEST12001420, (99%) (99%) WEAKLYSIMILAR TO D. MELANOGASTER PUTATIVE ORGANIC CATION TRANSPORTER - Homosapiens ptnr:SPTREMBL- DJ261K5.1 (NOVEL 305 305/305 305/305 2.9e-160ACC:Q9UJ10 ORGANIC CATION (100%) (100%) TRANSPORTER (BAC ORFRG331P03)) - Homo sapiens ptnr:SPTREMBL- 4921504E14R1K PROTEIN - 419166/317 219/317 3.3e-88 ACC:Q9D5Z0 Mus musculus (52%) (69%)

[0232] A multiple sequence alignment is shown in Table 13G, with theprotein of the inventin being shown on the first line in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 13F.

[0233] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 13H. TABLE 13H Patp BLASTP Analysis for NOV13 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAB43038 Human ORFX ORF2802 560 534/534534/534 1.3e-290 polypeptide sequence (100%) (100%) SEQ ID NO:5604 -Homo sapiens patp:AAM78367 Human protein SEQ ID NO 577 534/534 534/5341.3e-290 1029 - Homo sapiens (100%) (100%) patp:AAM00930 Human bonemarrow 584 532/535 532/535 1.7e-288 protein, SEQ ID NO: 406 - (99%)(99%) Homo sapiens patp:AAN79351 Human protein SEQ ID NO 585 528/536528/536 4.2e-285 2997 - Homo sapiens (98%) (98%) patp:AAM00982 Humanbone marrow 483 399/400 400/400 4.2e-219 protein, SEQ ID NO: 483 - (99%)(100%) Homo sapiens

[0234] Table 13I lists the domain description from DOMAIN analysisresults against NOV13. TABLE 131 Domain Analysis of NOV13 Pfam analysisModel Domain seq-f seq-t hmm-f hmm-t score E-value ABC-3 1/1 115 312 ..1 267 [] −189.9 4.6 Abi 1/1 348 442 .. 1 119 [] −20.1 1.9 sugar_tr 1/177 495 .. 1 488 [] 48.5 1.5e−10 Alignments of top-scoring domains:ABC-3: domain 1 of 1, from 115 to 312: score −189.9, E = 4.6qyefmqrAllasilvglacgiLGsFlVLRRqSLmGDAisHavLPGvA (SEQ ID NO: 168)|  ||+ +||+|+  | ++  ||     || +|  +++|   | |+| NOV13a 115QPLFMFGVLLGSVTFGYFSDRLG-----RRVVLW-ATSSSMFLFGIA 155LAffLginkSleipliGAflfglia....AvaigylkrnSrlkeDtaiGI ||+ +       + ++ |+ +++ 51 ++  +|+++|+++    |+ |   + 156AAFAVDYYT----FMAARFFLAMVAsgylVVGFVYVMEFIGMKSRTWASV 201vfssflAlGl11isiikgsnaaskvdLdhyLFGniLgisqqDliqiaiit ++||+|+| ||+ |+             ||   + +  + ++|++ +++ 202HLHSFFAVGTLLVALTG------------YL---VRTWWLYQMILSTVTV 236aiiLlllllfWkeLllitFDpdlAkViGlpvnflkllLliLlaltiVval +||+  +|   ++ |++        +| 237PFILCCWVLPETPFWLLS--------EG---------------------- 256qaVGyILViAlLitPAatArlltkslesmlliAsaiGvvssvaGlllSYy                    ++ +  + + + |    ++|+ +  ||| 257--------------------RYEEAQKIVDIMAICWNRASSCKLSELLSLD 286fd..tatGpvlVLiatllFlisflfa<- + ++++ +|+ |    | +|+  + + 287LQgpVSNSPTEVQKHNLSYLFYNWSI 312 Abi: domain 1 of 1, from 348 to 442:score −20.1, E = 1.9 lllilllvllaplaEElfFRGilltalerr.lkkrytlfgpllaiiis(SEQ ID NO:169) |++| +| + +      | +| +   +||+      ++ + +++++ NOV13a348 LFLLGVVEIPA----YTFVCIAMDKVGRRtVLA----YSLFCSALAC 386slifallhlanalellqllgnvliqpvlinwlqllytfllGlvlgllylr+++  +   +++|+               ++  +++ |++|  +||+|| 387GVVMVIPQKEYILG---------------VVTAMVGKFAIGAAFGLIYL- 420rtgsLlapilvHalnNligfill+21 - +|  | +  +| +| +  | +++ 421YTAELYP-TIVRSLAVGSGSMVC 442 sugar_tr: domain 1 of 1, from 77 to 495:score 48.5, E =1.5e−10 valvaalgGgflfGyDtgviggflalidflfrfglltssgalaelvg(SEQ ID NO:170) +  + ++ |   + ||  +  +++  +       +  +++ ++ NOV13a 77KKEFPCVDG---YIYDQNTWKSTAVTQW----NLVCDRKWLAM---- 112ystvltglvvsifflGrliGslfaGklgdrfGRkksllialvlfviGall       |+   |++| |+||+ +|+++||+||+  | +++  ++  ++ 113-------LIQPLFMFGVLLGSVTFGYFSDRLGRRVVLWATSSSMFLFGIA 155sgaapgytTiGlWafyllivGRvlvGlgvGgasvlvPmYisEiAPkalRG ++|         ++| ++++|+++ + + |  |+  +|+ |+   + | 156AAFAV---------DYYTFMAARFFLAMVASGYLVVGFVYVMEFIGMKSRT 197algslyqlaitiGilVAaiiglgl.nktnndsalnswgWRiplglqlvpa   +   ++ ++| |+ |++|+ ++ +  +            + +  + 198WASVHLHSFFAVGTLLVALTGThVrTWWLY------------QMILSTVT 235lllligilflPESPRwLvekgkleeArevLaklrgvedvdqeiqeikael++++++++ |||+|+||++ |++|||+++++   ++  ++ +   +   +| 236VPFILCCWLPETPFWLLSEGRYEEAQKIVDIMAKWNRASSCKLSELLSL 285ea....tvseekagkaswgelfrgrtrpkvrqrllmgvmlqafqQltGiN+ +++ ++|+++++|+     || +++   + +|+|++++++++ 286DLqgpvSNSPTEVQKHNLSYLFYNWS---ITKRTLTVWLIWFTG------ 326aifYYsptifksvGvsdsvasllvtiivgvvNf.vfTfvaLiflvDrfGR++ +|| ++   +  +++   +|  +++||| +++ |||     +|+ || 327SLGFYSFSLNSVNLGGNE---YLNLFLLGVVEIpAYTFVC--IAIVDKVGR 371RpllllGaagmaicflilgasigvallllnkpkdpsskaagivaivfill|+ |+ +++  |+++ ++        ++++|+         |+ +| +++ 372RTVLAYSLFCSALACGVV-------MVIPQKH--------YILGVVTAMV 406fiafFalgwGpipwvilsElFPtkvRskalalataanwlanfiigflfpy  ++++  +| |  ++++||+|| |||+| +   ++ +||+++++  | 407GKFAIGAAFGLIY-LYTAELYPTIVRSLAVGSGSMVCRLASILAP--FSV 453itgaiglalggyvflvfagllvlfilfvfffvPETkGrtLEeieelf+21 -*   +++|+    +++  +|+| ++|++ +  +++||| |+ | +  + 454DLSSIW----IFIPQLFVGTMALLSGVLTLKLPETLGKRL-ATTWEE 495

[0235] The sugar tranporter domain (IPR001066) consists of twelvetransmembrane domains and was initially identified in sugartransporters. This indicates that the sequence of the invention hasproperties similar to those of other proteins known to contain thisdomain and similar to the properties of these domains.

[0236] In 1994 the first member of the organic cation transporterfamily, designated as OCT1, was isolated from the rat kidney byexpression cloning. Rat (r)OCT1 is comprised of 556 amino acids with 12putative transmembrane domains. Northern blot analysis showed that rOCT1mRNA was expressed in the liver, kidney, and intestine. In the kidney,rOCT1 mRNA was detected in proximal tubules, glomeruli, and corticalcollecting ducts, but not in distal tubules. By immunohistochemicalanalysis, rOCT1 was localized to the basolateral membranes of S1 and S2segments of proximal renal tubules and the small intestine and liver.When expressed in oocytes, rOCT1 stimulated uptake of TEA, which wasinhibited by diverse organic cations. Electrophysiological experimentsusing rOCT1-expressing oocytes under voltage-clamped conditionsdemonstrated that positive inward currents were induced when TEA, NMN,choline, dopamine, or MPP were added to the bath medium, indicating thatrOCT1-mediated cation uptake is electrogenic.

[0237] Human (h) OCT1 is comprised of 554 amino acids and shows 78%identity with rOCT1. Its mRNA transcript was detected exclusively in theliver. There are distinct species differences in tissue distribution andhistochemical localization of OCT1. After expression in oocytes, hOCT1mediated the uptake of type 1 organic cations such as NMN, TEA, and MPP,suggesting that hOCT1 may primarily participate in hepatic excretion oforganic cations in humans. hOCT1-mediated MPP uptake was saturable witha Km value of 14.6 mmol/L and was sensitive to transmembrane potential.The type 2 hydrophobic cations such as vecuronium and decynium-22 aswell as the type 1 hydrophilic cations such as TEA and NMN inhibited MPPuptake. hOCT1 has lower binding affinity for several cations such asdecynium-22, tetrapentylammonium, quinine, and NMN than rOCT1,indicating species differences in the substrate specificity. The humangenes of hOCT1 and hOCT2 (also named SLC22A1 and SLC22A2) have beenlocalized in close proximity on chromosome 6q26.

[0238] Since OCT1 was cloned, other gene products with significanthomology to OCT1 have been identified. Using hybridization techniques,we isolated a cDNA encoding OCT2 from rat kidney. rOCT2 is comprised of593 amino acids with 12 proposed putative transmembrane domains showinga 67% identity to rOCT1. On Northern hybridization and RT-PCR analysis,the rOCT2 mRNA transcript was detected predominantly in the kidney, athigher levels in the medulla than the cortex, but not in the liver,lung, or intestine. When rOCT2 was expressed in oocytes, uptake of TEAwas suppressed by the replacement of Na+ with K+, suggesting that theuptake was membrane potential-dependent. Acidification of extracellularmedium resulted in a decreased uptake of TEA, whereas the efflux of TEAout of rOCT1- and rOCT2-expressing oocytes was not stimulated by theinward H+ gradient. To compare the functional characteristics of rOCT1and rOCT2, we established stable transfectants using MDCK cells. TEAuptake by both rOCT1 and rOCT2 transfectants grown on microporousmembrane filters was markedly enhanced when TEA was added to thebasolateral bath medium, but not to the apical medium. TEA uptake byboth transfectants was decreased by acidifying the medium pH, suggestingthat rOCT1- and rOCT2-mediated TEA transport were pH sensitive. Effluxof TEA out of the transfectants was unaffected or moderately inhibitedby acidification of the medium. Structurally diverse organic cations,including the type 1 cations such as MPP, cimetidine, NMN, nicotine, andprocainamide, and type 2 cations, such as quinine and quinidine,inhibited TEA uptake in the transfectants. Inhibition experimentssuggested that rOCT1 and rOCT2 had similar inhibitor binding affinitiesfor many compounds, but showed moderate differences in inhibitorsensitivity for several compounds such as MPP, procainamide, dopamine,and testosterone by a factor of 2 to 3. rOCT2 and hOCT2, which share 80%amino acid identity, have been shown to accept monoamineneurotransmitters such as dopamine, norepinephrine, epinephrine,5-hydroxytryptamine, and amantadine as substrates. These findings raisethe possibility that OCT2 plays a physiological role in renal handlingof some bioactive monoamines and implies that the transporter isindirectly involved in the physiological function of these monoaminessuch as renal tubular reabsorption of Na+.

[0239] Recently, it was reported that slices and isolated basolateralmembrane vesicles of male rat kidney showed a higher transport activityfor TEA than those of female rat kidney. The expression levels of rOCT2mRNA and the protein in the kidney of males were much higher than thosein females. There was no gender difference in mRNA expression levels ofrOCT1. These findings suggested that rOCT2 is responsible for the genderdifferences in renal basolateral membrane organic cation transportactivity.

[0240] A cDNA encoding an additional member of the OCT gene family,designated as OCT3, was isolated from the rat placenta. rOCT3 iscomprised of 551 amino acids with 12 putative transmembrane domains andshows 48% identity to rOCT1. Northern blot analysis indicated that rOCT3mRNA was detected most abundantly in the placenta and moderately in theintestine, heart, and brain. Expression of rOCT3 mRNA was comparativelylow in the kidney and lung, and it was not detected in the liver. Whenexpressed in HeLa cells and Xenopus oocytes, rOCT3 induced uptake of TEAand guanidine, which could be inhibited by MPP. Under voltage-clampedconditions, rOCT3-mediated TEA uptake evoked a potential-dependentinward current. The current induced by the TEA uptake was markedlyinfluenced by extracellular pH. However, such pH dependence of TEAuptake by rOCT3-expressing oocytes could not be confirmed under voltageclamp conditions. Therefore, rOCT3 appears to be a potential-sensitiveand pH gradient-independent organic cation transporter. Although thedistribution and localization of rOCT3 in the kidney have not yet beendetermined, it may also participate in the renal handling of a varietyof organic cations.

[0241] By their homology to OCT transporters, two additional members ofthe OCT gene family, named hOCTN1 (SLC22A4) and hOCTN2 (SLC22A5), havebeen identified. A cDNA encoding hOCTN1 was cloned from human fetalliver and encodes 551 amino acid residue protein with 11 putativetransmembrane domains and one nucleotide binding site motif. hOCTN1 mRNAwas found to be abundant in the kidney, trachea, bone marrow, fetalliver and several human cancer cell lines, but not in adult liver. Whenexpressed in HEK293 cells, hOCTN1 mediated saturable and pH-dependentuptake of TEA with higher activity at neutral and alkaline than atacidic pH. In addition, the efflux of TEA out of the cells waspH-dependent, with an accelerated rate at acidic external medium pH. TEAuptake was not influenced by membrane potential, and hOCTN1-mediated TEAuptake was inhibited by other organic cations such as cimetidine,procainamide, quinidine, quinine, and verapamil. When expressed inoocytes, hOCTN1 stimulated uptake of quinidine, verapamil, andzwitterionic L-carnitine. The functional role of OCTN1 in the renalsecretion of organic cations remains unknown.

[0242] hOCTN2 was identified as a homologue of hOCTN1 from human kidney.hOCTN2 cDNA encodes a 557-amino acid residue protein with 76% similarityto hOCTN1. hOCTN2 is strongly expressed in the kidney, trachea, spleen,bone marrow, skeletal muscle, heart, and placenta in adult humans. Whenexpressed in HEK293 cells, hOCTN2 mediated the uptake of L-carnitine ina Na+-dependent manner with a Km value of 4.3 mmol/L, whereas itmediated some minor uptake of TEA and guanidine. The physiologicalfunction of hOCTN2 is suggested to be a high-affinity Na+-carnitinecotransporter. It was reported that primary systemic carnitinedeficiency, which is an autosomal recessive disease characterized by lowserum and intracellular concentrations of carnitine, is caused bymutations in the hOCTN2 gene.

[0243] Interestingly, it was recently reported that rOCTN2 is aNa+-independent organic cation transporter as well as a Na+-dependentcarnitine transporter, which is expressed in the heart, kidney,placenta, and brain. In rat kidney, rOCTN2 mRNA is predominantlyexpressed in the cortex, while there is very little expression in themedulla. In the cortical region, rOCTN2 mRNA was found in the proximaland distal tubules. There have been two mutations reported that resultin amino acid substitution in OCTN2, P478L (hOCTN2) and L352R (mouseOCTN2). These mutations in hOCTN2 cause complete loss of carnitinetransport function. In contrast, only the M352R mutant appeared to beassociated with complete loss of organic cation transport function,whereas the P478L mutant had higher organic cation transport activitythan the wild-type transporter. These studies suggested that the bindingsites for carnitine and organic cations in OCTN2 exhibit significantoverlap but are not identical. Therefore, there may be clinicalimplications for pharmacotherapy in individual patients with primarycarnitine deficiency if the mutations in OCTN2 also affect organiccation transport activity.

[0244] The organic cation transporter family is critical in theelimination of many endogenous amines as well as drugs and environmentaltoxin. Members of this family are usually expressed in the kidney, liverand small intestine. Gründemann et al (Nature 372: 549-552, 1994)identified the first member of the organic cation transporter family,designated as OCT1, from the rat kidney by expression cloning. rOCT1 iscomprised of 556 amino acids with 12 putative transmembrane domains andis expressed in the liver, kidney, intestine and colon. When expressedin oocytes, rOCT1 stimulated uptake of TEA, which was inhibited bydiverse organic cations. Electrophysiological experiments usingrOCT1-expressing oocytes under voltage-clamped conditions demonstratedthat positive inward currents were induced when TEA, NMN, choline,dopamine, or BPP were added to the bath medium, indicating thatrOCT1-mediated cation uptake is electrogenic.

[0245] Human hOCT1 is comprised of 554 amino acids and shows 78%identity with rOCT1 (Zhang et al., Molec. Pharm. 51: 913-921, 1997). ItsmRNA transcript was detected exclusively in the liver. There aredistinct species differences in tissue distribution and histochemicallocalization of OCT1. After expression in oocytes, hOCT1 mediated theuptake of type 1 organic cations such as NMN, TEA, and MPP, suggestingthat hOCT1 may primarily participate in hepatic excretion of organiccations in humans. hOCT1 seems to differ in its substrate specificityrelative to rOCT1. The human genes of hOCT1 and hOCT2 (also namedSLC22A1 and SLC22A2) have been localized in close proximity onchromosome 6q26.

[0246] Since OCT1 was cloned, other gene products with significanthomology to OCT1 have been identified. rOCT2, isolated from rat kidney,has a 67% identity to rOCT1 (Okuda et al., Biochem Biophys Res Commun224(2):500-7, 1996). It is detected predominantly in the kidney, athigher levels in the medulla than the cortex, but not in the liver,lung, or intestine. rOCT2 seems to play a physiological role in renalhandling of some bioactive monoamines. A cDNA encoding an additionalmember of the OCT gene family, designated as OCT3, was isolated from therat placenta (Kekuda et al., J Biol Chem 273(26):15971-9, 1998). rOCT3is comprised of 551 amino acids with 12 putative transmembrane domainsand shows 48% identity to rOCT1. Northern blot analysis indicated thatrOCT3 mRNA was detected most abundantly in the placenta and moderatelyin the intestine, heart, and brain. Expression of rOCT3 mRNA wascomparatively low in the kidney and lung, and it was not detected in theliver. rOCT3 is a potential-sensitive and pH gradient-independentorganic cation transporter.

[0247] By their homology to OCT transporters, two additional members ofthe OCT gene family, named hOCTN1 (SLC22A4; Tamai et al., FEBS Lett419(1):107-11, 1997) and hOCTN2 (SLC22A5; Wu et al., Biochem Biophys ResCommun 246(3):589-95, 1998) have also been identified. hOCTN1 mRNA wasfound to be abundant in the kidney, trachea, bone marrow, fetal liverand several human cancer cell lines, but not in adult liver. hOCTN2 isstrongly expressed in the kidney, trachea, spleen, bone marrow, skeletalmuscle, heart, and placenta in adult humans. The physiological functionof hOCTN2 is suggested to be a high-affinity Na+-carnitinecotransporter. It has been reported that primary systemic camitinedeficiency, an autosomal recessive disease characterized by low serumand intracellular concentrations of carnitine, is caused by mutations inthe hOCTN2 gene (Wang et al., Hum Mutat 16(5):401-7, 2000).

[0248] NOV14

[0249] NOV14 includes two novel D-beta HydroxybutyrateDehydrogenase-like proteins disclosed below. The disclosed sequenceshave been named NOV14a and NOV14b. Unless specifically addressed asNOV14a or NOV14b, any reference to NOV14 is assumed to encompass allvariants.

[0250] NOV14a

[0251] A disclosed NOV14a nucleic acid of 1192 nucleotides (alsoreferred to as CG56001-01) (SEQ ID NO:31) encoding a novelD-beta-hydroxybutyrate dehydrogenase-like protein is shown in Table 14A.An open reading frame was identified beginning with an ATG initiationcodon at nucleotides 69-71 and ending with a TGA codon at nucleotides1098-1100. Putative untranslated regions upstream from the initiationcodon and downstream from the termination codon are underlined. Thestart and stop codons are in bold in Table 14A. TABLE 14A NOV14anucleotide sequence (SEQ ID NO:31)TGCTGAGGGTGCATTTATGTTTCAGAACCACCGGGAGGAACTGGGCCATT CTAACACCCGTTGCTACCATGCTGGCCACCCGCCTCTCCAGACCCCTGTCACGGCTCCCAGGAAAAAACCCTAAGTGCCTGTGATAGAGAAAATGGAGCAAGGCGCCCACTATTGCTTGGTTCTACTTCCTTTATCCCGATTGGCCGTCGGACTTATGCCAGTGCGGCGGAGCCGGTGAGTGGAAAAGCTGTCCTGGTCACAGGCTGTGACTCTGGATTTGGGTTCTCATTGGCCAAGCATCTGCATTCAAAAGGCTTCCTTGTGTTTGCTGGCTGCTTGATGAAGGACAAAGGCCATGATGGGGTCAAGGAGCTGGACAGCCTAAACAGTGACCGATTGAGAACCGTCCAGCTCAATGTCTGCAGCAGCGAAGAGGTGGAGAAAGTGGTGGAGATTGTCCGCTCGAGCCTGAAGGACCCTGAGAAAGGTATGTGGGGCCTCGTTAACAATGCCGGCATCTCAACGTTCGGGGAGGTGGAGTTCACCAGCCTGGAGACCTACAAGCAGGTGGCAGAAGTGAACCTTTGGGGCACAGTGCGGATGACGAAATCCTTTCTCCCCCTCATCCGAAGGGCCAAAGGTCGCGTCGTCAATATCAGCAGCATGCTGGGCCGCATGGCCAACCCGGCCCGCTCCCCGTACTGCATCACCAAGTTCGGGGTAGAGGCTTTCTCGGACTGCCTGCGCTATGAGATGTACCCCCTGGGCGTGAAGGTCAGCGTGGTGGAGCCCGGCAACTTCATCGCTGCCACCAGCCTTTACAGCCCTGAGAGCATTCAGGCCATCGCCAAGAAGATGTGGGAGGAGCTGCCTGAGGTCGTGCGCAAGGACTACGGCAAGAAGTACTTTGATGAAAAGATCGCCAAGATGGAGACCTACTGCAGCAGTGGCTCCACAGACACGTCCCCTGTCATCGATGCTGTCACACACGCCCTGACCGCCACCACCCCCTACACCCGCTACCACCCCATGGACTACTACTGGTGGCTGCGAATGCAGATCATGACCCACTTGCCTGGAGCCATCTCCGACATGATCTACATCCGCTG AAGAGTCTCGCTGTGGCCTCTGTCAGGGATCCCTGGTGGAAGGGGAGGGGAGGGAGGAACCCATATAGTCAACTCTTGATTATCCACGTGTGG

[0252] The human D-beta-hydroxybutyrate dehydrogenase-like NOV14adisclosed in this invention maps to chromosome 3.

[0253] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 958 of 1145 bases(83%) identical to a gb:GENBANK-ID:RATDBHYDEH|acc:M89902.1 mRNA fromRattus norvegicus (Sprague-Dawley D-beta-hydroxybutyrate dehydrogenasemRNA, complete cds).

[0254] A disclosed NOV14a polypeptide (SEQ ID NO:32) encoded by SEQ IDNO:31 has 343 amino acid residues and is presented in Table 14B usingthe one-letter code. Although SignalP suggests that the humanD-beta-hydroxybutyrate dehydrogenase may have a signal peptide, Psortpredicts that it is localized in to mitochondria. Because it is similarto the human hydroxybutyrate dehydrogenase family, some members of whichare expected to have mitochondrial localization. Therefore it is likelythat this novel human D-beta-hydroxybutyrate dehydrogenase is availableat the same sub-cellular localization and hence accessible to adiagnostic probe and for various therapeutic applications. Nonetheless,the SignalP, Psort and/or Hydropathy results predict that NOV14a islikely to be localized to the mitochondrial matrix space with acertainty of 0.6723. In an alternative embodiment, NOV14 is likely to belocalized to the microbody (peroxisome) with a certainty of 0.3942, orto the mitochondrial inner membrane with a certainty of 0.3622, or tothe mitochondrial intermembrane space with a certainty of 0.3622.According to SignalP data the most likely cleavage site is between aminoacids 12 and 13, i.e., at the dash in the sequence LSR-LP. TABLE 14BNOV14a protein sequence (SEQ ID NO:32)MLATRLSRPLSRLPGKTLSACDRENGARRPLLLGSTSFIPIGRRTYASAAEPVSGKAVLVTGCDSGFGFSLAKHLHSKGFLVFAGCLMKDKGHDGVKELDSLNSDRLRTVQLNVCSSEEVEKVVEIVRSSLKDPEKGMWGLVNNAGISTFGEVEFTSLETYKQVAEVNLWGTVRMTKSFLPLIRRAKGRVVNISSMLGRMANPARSPYCITKFGVEAFSDCLRYEMYPLGVKVSVVEPGNFIAATSLYSPESIQAIAKKMWEELFEVVRKDYGKKYFDEKIAKMETYCSSGSTDTSPVIDAVTHALTATTPYTRYHPMDYYWWLRMQIMTHLPGAISDMIYIR

[0255] The full amino acid sequence of the protein of the invention wasfound to have 297 of 342 amino acid residues (86%) identical to, and 313of 342 amino acid residues (91%) similar to, the 344 amino acid residueptnr:SWISSPROT-ACC:P29147 protein from Rattus norvegicus (Rat)(D-BETA-HYDROXYBUTYRATE DEHYDROGENASE PRECURSOR (EC 1.1.1.30) (BDH)(3-HYDROXYBUTYRATE DEHYDROGENASE)).

[0256] The human D-beta-hydroxybutyrate dehydrogenase disclosed in thisinvention is expressed in at least the following tissues: brain, eye,colon, kidney, liver, spleen, lung, breast, ovary, testis, genitourinarytrack, lymph, T-cell, B-cell. In addition, the sequence is predicted tobe expressed in the heart because of the expression pattern of(GENBANK-ID: gb:GENBANK-ID:RATDBHYDEH|acc:M89902.1) a closely relatedSprague-Dawley D-beta-hydroxybutyrate dehydrogenase mRNA, complete cdshomolog in species Rattus norvegicus.

[0257] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from diabetes, obesity, and otherdiseases, disorders and conditions of the like.

[0258] NOV14b

[0259] A disclosed NOV14b nucleic acid of 1166 nucleotides (alsoreferred to as CG56001-02) (SEQ ID NO:33) encoding a novelD-beta-hydroxybutyrate dehydrogenase-like protein is shown in Table 14C.An open reading frame was identified beginning with an ATG initiationcodon at nucleotides 69-71 and ending with a TGA codon at nucleotides1098-1100. Putative untranslated regions upstream from the initiationcodon and downstream from the termination codon are underlined. Thestart and stop codons are in bold in Table 14C. TABLE 14C NOV14bnucleotide sequence (SEQ ID NO:33)TGCTGAGGGTGCATTTATGTTTCAGAACCACCGGGAGGAACTGGGCCATT CTAACACCCGTTGCTACCATGCTGGCCACCCGCCTCTCCAGACCCCTGTCACGGCTCCCAGGAAAAACCCTAAGTGCCTGTGATAGAGAAAATGGAGCAAGACGCCCACTATTGCTTGGTTCTACTTCCTTTATCCCGATTGGCCGTCGGACTTATGCCAGTGCGGCGGAGCCGGTTGGCAGCAAAGCTGTCCTGGTCACAGGCTGTGACTCTGGATTTGGGTTCTCATTGGCCAAGCATCTGCATTCAAAAGGCTTCCTTGTGTTTGCTGGCTGCTTGATGAAGGACAAAGGCCATGATGGGGTCAAGGAGCTGGACAGCCTAAACAGTGACCGATTGAGAACCGTCCAGCTCAATGTCTGCAGCAGCGAAGAGGTGGAGAAAGTGGTGGAGATTGTCCGCTCGAGCCTGAAGGACCCTGAGAAAGGCATGTGGGGCCTCGTTAACAATGCCGGCATCTCAACGTTCGGGGAGGTGGAGTTAACCAGCCTGGAGACCTACAAGCAGGTGGCAGAAGTGAACCTTTGGGGCACAGTGCGGATGACGAAATCCTTTCTCCCCCTCATCCGAAGGGCCAAAGGCCGCGTCGTCAATATCAGCAGCATGCTGGGCCGCATGGCCAACCCGGCCCGCTCCCCGTACTGCATCACCAAGTTCGGGGTAGAGGCTTTCTCGGACTGCCTGCGCTATGAGATGTACCCCCTGGGCGTGAAGGTCAGCGTGGTGGAGCCCGGCAACTTCATCGCTGCCACCAGCCTTTACAGCCCTGAGAGCATTCAGGCCATCGCCAAGAAGATGTGGGAGGAGCTGCCTGAGGTCGTGCGcAGGACTACGGCAAAGAAGTACTTTGATGAAAAGATCGCCAAGATGGAGACCTACTGCAGCAGTGGCTCCACAGACACGTCCCCTGTCATCGATGCTGTCACACACGCCCTGACCGCCACCACCCCCTACACCCGCTACCACCCCATGGACTACTACTGGTGGCTGCGAATGCAGATCATGACCCACTTGCCTGGAGCCATCTCCGACATGATCTACATCCGCTGAAGAGTCTCGCTGTGGCCTCTGTAAGGGATTCCTGGTGGAAGGGGAGGGGA GGGAGGAACCCATATA

[0260] The human D-beta-hydroxybutyrate dehydrogenase-like NOV14bdisclosed in this invention maps to chromosome 3.

[0261] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 933 of 1108 bases(84%) identical to a gb:GENBANK-ID:RATDBHYDEH|acc:M89902.1 mRNA fromRattus norvegicus (Sprague-Dawley D-beta-hydroxybutyrate dehydrogenasemRNA, complete cds).

[0262] A disclosed NOV14b polypeptide (SEQ ID NO:34) encoded by SEQ IDNO:33 has 343 amino acid residues and is presented in Table 14D usingthe one-letter code. SignalP, Psort and/or Hydropathy results predictthat NOV14a is likely to be localized to the mitochondrial matrix spacewith a certainty of 0.6723. In an alternative embodiment, NOV14 islikely to be localized to the microbody (peroxisome) with a certainty of0.3942, or to the mitochondrial inner membrane with a certainty of0.3622, or to the mitochondrial intermembrane space with a certainty of0.3622. According to SignalP data the most likely cleavage site isbetween amino acids 12 and 13, i.e., at the dash in the sequence LSR-LP.TABLE 14D NOV14b protein sequence (SEQ ID NO:34)MLATRLSRPLSRLPGKTLSACDRENGARRPLLLGSTSFIPIGRRTYASAAEPVGSKAVLVTGCDSGFGFSLAKHLHSKGFLVFAGCLMKDKGHDGVKELDSLNSDRLRTVQLNVCSSEEVEKVVEIVRSSLKDPEKGMWGLVNNAGISTFGEVEFTSLETYKQVAEVNLWGTVRMTKSFLPLIRRAKGRVVNISSMLGRMANPARSPYCITKFGVEAFSDCLRYEMYPLGVKVSVVEPGNFIAATSLYSPESIQAIAKKMWEELPEVVRKDYGKKYFDEKIAKMETYCSSGSTDTSPVIDAVTHALTATTPYTRYHPMDYYWWLRMQIMTHLPGAISDMIYIR

[0263] The full amino acid sequence of the protein of the invention wasfound to have 331 of 344 amino acid residues (96%) identical to, and 333of 344 amino acid residues (96%) similar to, the 344 amino acid residueptnr:SWISSNEW-ACC:Q02338 protein from Homo sapiens (Human)(D-BETA-HYDROXYBUTYRATE DEHYDROGENASE PRECURSOR (EC 1.1.1.30) (BDH)(3-HYDROXYBUTYRATE DEHYDROGENASE)).

[0264] The D-BETA-HYDROXYBUTYRATE DEHYDROGENASE PRECURSOR-like genedisclosed in this invention is expressed in at least the followingtissues: brain, eye, colon, kidney, liver, spleen, lung, breast, ovary,testis, genitourinary track, lymph, T-cell, B-cell. Expressioninformation was derived from the tissue sources of the sequences thatwere included in the derivation of the sequence of CuraGen Acc. No.CG56001-02. The sequence is predicted to be expressed in the followingtissues because of the expression pattern of (GENBANK-ID:gb:GENBANK-ID:RATDBHYDEH|acc:M89902.1) a closely related Sprague-DawleyD-beta-hydroxybutyrate dehydrogenase mRNA, complete cds homolog inspecies Rattus norvegicus:heart.

[0265] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: diabetes, obesity as wellas other diseases, disorders and conditions.

[0266] NOV14a and NOV14b share a high degree of homology as is shown inthe amino acid alignment in Table 14E.

[0267] In a search of public sequence databases, NOV14 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 14F. TABLE 14F BLASTP results for NOV14 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SPTREMBL- HYPOTHETICAL 343 341/343 341/343 2.0e- ACC:Q9BRZ4 38.2EDA PROTEIN - (99%) (99%) 182 Homo sapiens ptnr:SPTREMBL- UNKNOWN(PROTEIN 343 340/343 341/343 4.2e- ACC:Q96ET1 FOR MGC:9788) - (99%)(99%) 182 Homo sapiens ptnr: D-beta-hydroxybut- 344 329/344 331/3441.0e- SWISSNEW- yrate dehydrogenase, (95%) (96%) 173 ACC:Q02338mitochondrial precursor (EC 1.1.1.30) (BDH) (3- hydroxybutyratedehydrogenase) - Homo sapiens ptnr:pir- 3-hydroxybutyrate 343 319/333321/333 1.1e- id:A42845 dehydrogenase (EC (95%) (96%) 169 1.1.1.30) -human ptnr: D-beta-hydroxybutyrate 344 297/342 313/342 3.6e- SWISSNEW-dehydrogenase, (86%) (91%) 160 ACC:P29147 mitochondrial precursor (EC1.1.1.30) (BDH) (3- hydroxybutyrate dehydrogenase) - Rattus norvegicus

[0268] A multiple sequence alignment is shown in Table 14G, with theprotein of the invention being shown on the first line in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 14F.

[0269] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 14H. TABLE 14H Patp BLASTP Analysis for NOV14 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAM78804 Human protein SEQ ID NO 343 341/343341/343 1.6e-182 1466 - Homo sapiens (99%) (99%) patp:AAM79788 Humanprotein SEQ ID NO 404 323/334 324/334 3.0e-172 3434 - Homo sapiens (96%)(97%) patp:AAW88492 Human liver clone 317 117/288 177/288 1.8e-48HP01299-encoded (40%) (61%) polypeptide - Homo sapiens patp:AAB56678Human prostate cancer 378 116/288 176/288 6.0e-48 antigen protein (40%)(61%) sequence SEQ ID NO:1256 - Homo sapiens patp:AAW18334 Murine liverp32 11- 316 109/260 156/260 1.2e-47 cis-retinol (41%) (60%)dehydrogenase - Mus musculus

[0270] Table 14I lists the domain description from DOMAIN analysisresults against NOV14. TABLE 14I Domain Analysis of NOV14 Pfam analysisModel Domain seq-f seq-t hmm-f hmm-t score E-value adh_short 1 1 54 336.. 1 271 [] 268.1 1.2e-76 Alignments of top-scoring domains: adh_short:domain 1 of 1, from 54 to 336: score 268.1, E = 1.2e−76tgKvaLvTGassGIGlaiAkrLakeGakVvvvdrreekaeqvaaelk (SEQ ID NO: 176)+||++||||++||+|+ +||+|+++|+ |+++++ ++|+  +++|| NOV14a 54SGKAVLVTGCDSGFGFSLAKHLHSKGFLVFAGCLMKDKGHDGVKELD 100aelGdralfiqlDvtdeeqvkaavaqaverlGd...rlDvLVNNAGilgp+++ ||++++||+|++ |+|+++|+ +++ | |++++ ++|||||||+++ 101SLNSDRLRTVQLNVCSSEEVEKVVEIVRSSLKDpekGMWGLVNNAGISTF 150gppfeelseedwervidvNltGvflltqavlpamdhmlkrkgGrIvNisS|+++   |+|++++| +|||+|++++|+++||    +++|++||+||||| 151GEVEF-TSLETYKQVAELWGTVRMTKSFLP----LIRRAKGRVVNISS 195vaGlnvgvpglsaYsASKaavigltrsLAlElaphgtgIrVnavaPGgvd+ |+ +++|++|+|+ +|++|++++++|+ |++| |  ++|++| || + 196MLGR-MANPARSPYCITKFGVEAFSDCLRYEMYPLG--VKVSVVEPGNFI 242T..dmtkalrsrlieakkk.v.re.v.adiadpeleerits.titplgry  +++    + + |++|++++ +| |++|+ +++++|+|++ ++ ++  + 243AatSLYSPESIQAIAKKMWeElPEvVrKDYGKKYFDEKIAKmET-YCSSG 291gvtpeeianavlfLasdgasys...........vtgqtlnvdggl<-* ++ + + +|| + +++  +|++ ++ +     ++  +++++  |++ 292STDTSPVIDAVTHALTATTPYTryhpmdyywwlRMQIMTHLPGAI 336

[0271] The short-chain dehydrogenases/reductases family (SDR) is a verylarge family of enzymes, most of which are known to be NAD- orNADP-dependent oxidoreductases. As the first member of this family to becharacterized was Drosophila alcohol dehydrogenase, this family used tobe called ‘insect-type’, or ‘short-chain’ alcohol dehydrogenases. Mostmembers of this family are proteins of about 250 to 300 amino acidresidues. Most dehydrogenases possess at least two domains, the firstbinding the coenzyme, often NAD, and the second binding the substrate.This latter domain determines the substrate specificity and containsamino acids involved in catalysis. Little sequence similarity has beenfound in the coenzyme binding domain although there is a large degree ofstructural similarity, and it has therefore been suggested that thestructure of dehydrogenases has arisen through gene fusion of a commonancestral coenzyme nucleotide sequence with various substrate specificdomains.

[0272] This family should always be found adjacent to[INTERPRO:IPR002198], which is a general family of Short-chaindehydrogenases and reductases. A match to this extension indicates thatthe protein is probably an alcohol dehydrogenase.

[0273] This indicates that the sequence of the invention has propertiessimilar to those of other proteins known to contain this/these domain(s)and similar to the properties of these domains.

[0274] (R)-3-hydroxybutyrate dehydrogenase (BDH) is a mitochondrialmembrane enzyme with an absolute and specific requirement forphosphatidylcholine, which acts as an allosteric activator of BDHenzymatic activity. BDH has served as a prototype for lipid-requiringenzymes. By screening a human heart cDNA library with degenerateoligonucleotides based on peptide sequences from purified bovine BDH,cDNAs encoding BDH (fragment, missing N-terminal) have been isolated.The deduced 343-amino acid protein contains a 46-residue leader peptide,which is cleaved to produce the mature form. Sequence analysis revealedthat the first two-thirds of the BDH protein is homologous toshort-chain alcohol dehydrogenases (SCADHs), with the homologyencompassing the putative coenzyme-binding and active sites of theSCADHs; this region of BDH also has the predicted secondary structuremotif of alternating alpha-helices and beta-sheets that ischaracteristic of SCADHs. The data suggests that the remainder of theBDH protein contains elements that form the substrate- and lipid-bindingsites. Northern blot analysis revealed that BDH is expressed in rabbitheart tissue.

[0275] The novel human D-beta-hydroxybutyrate dehydrogenase Protein ofthe invention has 95% homology to (R)-3-hydroxybutyrate dehydrogenase(BDH) described by Marks et al. Therefore it is anticipated that thisnovel protein has a role in the regulation of essentially all cellularfunctions and could be a potentially important target for drugs. Suchdrugs may have important therapeutic applications, such as treatingdiabetes and obesity diseases. See, Marks, A. R., et al., J. Biol. Chem.267: 15459-15463, 1992.

[0276] NOV15

[0277] NOV15 includes four novel TEN-M3-like proteins disclosed below.The disclosed sequences have been named NOV15a, NOV15b, NOV15c, andNOV15d. Unless specifically addressed as NOV15a, NOV15b, NOV15c, orNOV15d, any reference to NOV15 is assumed to encompass all variants.

[0278] NOV15a

[0279] A disclosed NOV15a nucleic acid of 8675 nucleotides (alsoreferred to as SC145665404_A or CG55069-01) (SEQ ID NO:35) encoding anovel TEN-M3-like protein is shown in Table 15A. An open reading framewas identified beginning with an ATG initiation codon at nucleotides151-153 and ending with a TAA codon at nucleotides 8326-8328. Putativeuntranslated regions upstream from the initiation codon and downstreamfrom the termination codon are underlined and the start and stop codonsare in bold in Table 15A. TABLE 15A NOV15a nucleotide sequence (SEQ IDNO:35)TTTGGCCTCGGGCCAGAATTCGGCACGAGGGGTCTGGAGCTTGGAGGAGAAGTCTGAACTAAGGATAAACTAAGAGAGGCCAATGAGACTTGAACCCTGAGCCTAAGTTGTCACCAGCAGGACTGATGTGACACACAGAAGGAATGAAGT ATGGATGTGAAGAACGCAGGCCTTACTGCTCCCTGACCAAGAGCAGACGAAGAGAAGGAACGGCGCTACACAAATTCCTCCGCAGACAATGAGGAGTGCCGGGTACCCACACAGAAGTCCTACAGTTCCAGCGAGACATTGAAAGCTTTTGATCATGATTCCTCGCGGCTGCTTTACGGCAACAGAGTGAAGGATTTGGTTCAAGAGAAGCAGACGAGTTCACTAGACAAGGACAGAATTTTACCCTAAAGGCAGTTAGGAGTTTGTGAACCAGCAACTCCAAGAGGACTGGCATTTTGTGCGGAAATGGGGCTCCCTCACAGAGGTTACTCTATCAGTGCAGGGTCAGATGCTGATACTGAAAATGAAGCAGTGATGTCCCCAGAGCATGCCATGAGACTTTGGGGCAGGGGGGTCAAATCAGGCCGCAGCTCCTGCCTGTCAAGTCGGTCCAACTCAGCCCTCACCCTGACAGATACGGAGCACGAAAACAAGTCCGACAGTGAGAATGAGCAACCTGCAAGCAATCAAGGCCAGTCTACCCTGCAGCCCTTGCCGCCTTCCCATAAGCAGCACTCTGCACAGCATCATCCATCCATCACTTCTCTCAACAGAAACTCCCTGACCAATAGAAGGAACCAGAGTCCGGCCCCGCCGGCTGCTTTGCCCGCCGAGCTGCAAGAAACACCCGAGTCCGTCCAGCTGCAGGACAGCTGGGTCCTTGGCAGTAATGTACCACTGGAAAGAAGGCATTTCCTATTCAAAACAGGAACAGGTACAACGCCACTGTTCAGTACTGCAACCCCAGGATACACAATGGCATCTGGCTCTGTTTATTCACCACCTACTCGGCCACTACCTAGAACACCCTATCAAAGAAGTGCTTTTAAATTCAAGAAGTCTTCAAAGTACTGTAGCTGGAAATGCACTGCACTGTGTGCCGTAGGGGTCTCGGTGCTCCTGGCAATACTCCTGTCTTATTTTATAGCAATGCATCTCTTTGGCCTCAACTGGCAGCTACAGCAGACTGAAAATGACACATTTGAGAATGGAAAAGTGAATTCTGATACCATGCCAACAAACACTGTGTCATTACCTTCTGGAGACAATGGAAAATTAGGTGGATTTACGCAAGAAAATAACACCATAGATTCCGGAGAACTTGATATTGGCCGAAGAGCAATTCAAGAGATTCCTCCCGGGATCTTCTGGAGATCACAGCTCTTCATTGATAAGCCAAAGTTTCTTAAATTCAATATCTCTCTTCAGAAGGATGCATTGATTGGAGTATATGGCCGGAAGAAGTTACCGCCTTCCCATACTCAGTCCTCCCCCCAGTATGACTTCGTGGAGCTCCTGGATGGCAGCAGGCTGATTGCCAGAGAGAAGCGGAGCCTGCTTGAGACGGAGAGAGCCGGGCGGCAGGCGAGATCCGTCAGCCTTCATGAGGCCGGCTTTATCCAGTACTTGGATTCTGGAATCTGGCATCTGGCTTTTTATAATGATGGGAAAAATGAAGAGCAGGTGTCTTTTAATACCATTGTTATAGAGTCTGTGGTGGAATGTCCCCGAAATTGCCATGGAAATGGAGAATGCGTTTCTGGAACTTGCCATTGTTTTCCAGGATTTCTGGGTCCGGATTGTTCAAGAGCCGCCTGTCCAGTGTTATGTAGTGGCAACGGGCAGTACTCCAAGGGCCGCTGCCTGTGTTTCAGCGGCTGGAAGGGCACCGAGTGTGATGTGCCGACTACCCAGTGTATTGACCCACAGTGTGGGGGTCGTGGGATTTGTATCATGGGCTCCTGTGCTTGCAGCTCAGGATACAAAGGAGAAAGTTGTGAAGAAGCTGACTGTATAGACCCTGGGTGTTCTAATCATGGTGTGTGTATCCACGGGGAATGTCACTGCAGTCCAGGATGGGGAGGTAGCAATTGTGAAATACTGAAGACCATGTGTCCAGACCAGTGCTCCGGCCACGGAACGTATCTTCAAGAAAGTGGCTCCTGCACGTGTGACCCTAACTGGACTGGCCCAGACTGCTCAAACGAAATATGTTCTGTGGACTGTGGCTCACACGGCGTTTGAATGGGGGGGACGTGTCGCTGTGAAGAAGGCTGGACGGGCCCAGCCTGTAATCAGAGAGCCTGCCACCCCCGCTGTGCCGAGCACGGGACCTGCAAGGATGGCAAGTGTGAATGCAGCCAGGGCTGGAATGGAGAGCACTGAACTATCGCTCACTATTTGGATAAGATAGTTAAGACAAAGATAGGATATAAAGAGGGTTGTCCTGGTCTGTGCAACAGCAATGGAAGATGTACCCTGGACCAAAATGGCGGACATTGTGTGTGCCAGCCTGGATGGAGAGGAGCAGGCTGTGACGTAGCCATGGAGACTCTTTGCACAGATAGAAGGACAAATGAAGGAAATGGACTCATTGACTGCATGGATCCCGATTGCTGCCTACAGAGTTCCTGCCAGAATCAGCCCTATTGTCGGGGACTGCCGGATCCTCAGGACATCATTAGCCAAAGCCTTCATCGCCTTCTCAAGCAAGCTGCCAAATCCTTTTATGATCGAATCAGTTTCCTTATAGGATCTGATAGCACCCATGTTATACCTGGAGAAGTCCTTTCAATAAAGAGCCTTGCATCTGTCATCAGAGGCCAAGTACTGACTGCTGATGGAACTCCACTTATTGGAGTAAATGTCTCGTTTTTCCATTACCCAGAATATGGATATACTATTACCCGCCAGGACGGAATGTTTGAACTTGGTGGCAATGGTGGGGCCTCTCTACTTTGGTATTTGAACGATCCCCATTCCTCAACTCAGTATCATACTGTGTGGATTCAATGGAATGTCTTTTATGTGATGGATACCCTAGTCATGGAGAAAGAAGAGAATGACATTCCCAGCTGTGATCTGAGTGGATTCGTGAGGCCAATCCCATCATTGTGTCATCACCTTTATCAACCTTTTTAAGATCTTCTCCTGAAAGACAGTCCCATCATTCCCGAAACACAGGTACTCCACGAGGAAACTACAATTCCAGGAAACAGATTTGAACTCTCCTACTTGAGTTCCAGAGCTGCAGGGTATAAGTCAGTTCTCAAGATAACCATGACCCAGTCTATTATTCCATTTAATTTAATGAAGGTTCATCTTATGGTAGCTGTAGTAGGAAGACTCTTCCAAAAGTGGTTTCCTGCCTCACCAAACTTGGCCTAATACTTTCATAATGGGATAAACAGATGCATATAATCAGAAGTCTATGGTCTATCTGAAGCTGTTGTGTCAGTTGGATATGAGTATGAGTCGTGTTTGGACCTGACTCTGTGGGAAAAGAGGACTGCCATTCTGCAGGGCTATGAATTGGATGCGTCCAACATGGGTGGCTGGAAATTAGATAAAAATCACGTGCTGGATGTACAGAACGGTATACTGTACAAGGGAACGGGGAAAACCAGTTCATCTCCAAAGCAGCCTCCAGTCGTGAGTAGCATCATGGGCAATGGGCGAAGGCGCAGCATTTCCTGCCCCAGTTGCAATGGTCAAGCTGATGGTAACAAGTTACTGGCCCCAGTGGCGCTAGCTTGTGGGATCGATGGCAGTCTGTACGTAGGCGATTTCACTACGTGCGGCGGATATTCCCCTTCTGGAATGTAACAAGTGTCTTAGAACTAAAGAAATAAAGATTTTAGACATAGCAGCAACCCAGCTCATAGATACTACCTTGCAACGGATCCAGTCACGGGAGATCTGTACGTTTCTGACACAAACACCCGCAGAATTTATCGCCCAAAGTCACTTACGGGGGCAAAAGACTTGACTAAAAATGCAGAAGTCGTCGCAGGGACAGGGGAGCAATGCCTTCCGTTTGACGAGGCGAGATGTGGGGATGGAGGGAAGGCCGTGGAAGCCACACTCATGAGTCCCAAAGGAATGGCAGTTGATAAGAATGGATTAATCTACTTTGTTGATGGAACCATGATTAGGAAAGTTGACCAAAAATGGAATCATATCAACTCTTCTGGGCTCTACGATTTGACTTCAGCCAGACCTTTAACTTGTGACACCAGCATGCACATCAGCCAGGTACGTCTGGAATGGCCCACTGACCTAGCCATTAACCCTATGGATAACTCCATTTATGTCCTGGATAATAATGTAGTTTTACAGATCACTGAAAATCGTCAAGTTCGCATTGCTGCTGGACGGCCCATGCACTGTCAGGTTCCCGGAGTGGAATATCCTGTGGGGAAGCACGCGGTGCAGACAACACTGGAATCAGCCACTGCCATTGCTGTGTCCTAAAGTGGGGTCCTGTACATTACTGAAACTGATGAGAAGAAATTAACCGGATAAGGCAGGTCACAAACAGATGGAAGAATCTCCTTAGTGGCCGGAATACCTTCAGAGTGTGACTGCAAAAATGATGCCAACTGTGACTGTTACAAGAGTGGAGATGGCTACGCCAAGGATGCCAAACTCAGTGCCCCATCCTCCCTGGCTGCTTCTCCAGATGGTACACTGTATATTGCAGATCTAGGGAATATCCGGATCCGGGCTGTGTCAAAGAATAAGCCTTTACTTAACTCTATGAACTTCTATGAAGTTGCGTCTCCAACTGATCAAGAACTCTACATCTTTGACATCAATGGTACTCACCAATATACTGTAAGTTTAGTCACTGGTGATTACCTTTACAATTTTAGCTACAGCAATGACAATGATATTACTGCTGTGACAGACAGCAATGGCAACACCCTTAGAATTAGACGGGACCCAAATCGCATGCCAGTTCGAGTGGTGTCTCCTGATAACCAAGTGATATGGTTGACAATAGGAACAAATGGATGTTTGAAAGGCATGACTGCTCAAGGACTGGAATTAGTTTTGTTTACTTACCATGGCAATAGGTGGCCTTTTAGCCACTAAAAGTGATGAACTGGATGGACAACGTTTTTTGACTATGACAGTGAAGGTCGTCTGACAAATGTTACGTTTCCAACTGGAGTGGTCACAAACCTGCATGGGGACATGGACAAGGCTATCACAGTGGACATTGAGTCATCTAGCCGAGAAGAAGATGTCAGAATCACTTCAAATCTGTCCTCGATCGATTCTTTCTACACCATGGTTCAGATCAGTTAAGAAACAGCTACAAAGATTGGTTATGACGGCTCCCTCAGAATTATCTACGCCAGTGGCCTGGAACTCACACTACAAACAGAGCCGCACGTTCTGGCTGGCACCGCTAATCCGACGGTTGCCAAAGAAACATGACTTTGCCTGGCGAGAAACGGTCAAAACTTGGTGGAATGGAGATTCCGGAAAAGCAAGCCCCAAGGGAAAGTCAATGTCTTTGGCCGCAAGCTCAGGGTTAATGGCAGAAACCTCCTTTCAGTTGACTTTGATCGAACAACAAAGACAGAAAAGATCTATGACGACCACCGTAAATTTCTACTGAGGATCGCCTACGACACGTCTGGGCACCCGACTCTCTGGCTGCCAAGCAGCAAGCTGATGGCCGTCAATGTCACCTATTCATCCACAGGTCAAATTGCCAGCATCCAGCGAGGCACCACTAGCGAGAAAGTAGATTATGACGGACAGGGGAGGATCGTGTCTCGGGTCTTTGCTGATGGTAAAACATGGAGTTACACATATTTAGAAAAGTCCATGGTTCTTCTGCTTCATAGCCAGCGGCAGTACATCTTCGAATACGATATGTGGGACCGCCTGTCTGCCATCACCATGCCCAGTGTGGCTCGCCACACCATGCAGACAATCCGATCCATTGGCTACTACCGCACATATACAACCCCCCGGAAGCAACGCCTCAATCATAAACGGACATACAACGAGGAAGGGCTGCTTCTACAACAGCTTTCTTGGGTACAAGTCGGAGGGGTCTTATTCAATACAGAAAGGAAGACTAGGCTCTCAGAAATTTTATATGATAGCACAAGAGTCAGTTTTACCTATGATGAAACAGCAGGAGTCCTAAAGACAGTAAACCTCCAGAGTGATGGTTTTATTTGCACCATTAGATACAGGCAAATTGGTCCCCTGATTGACAGGCAGATTTTCCGCTTTAGTGAGATGGGATGGTAAATGCAAGATTTGACTATAGCCTATGACAAAAGCTTTCGAGTGACCAGCATGCAGGGTGTGATCAATGAAACGCCACTGCCTATTGATCTGTATCAGTTTGATGACATTTCTGGCAAGTTGAGCAGTTTGGAAGTTTGGAGTTATATATTATGATATTAAACAAAGATCATTTCTACAGCTGTAATGACCTATACGAGCACTTTGATGCTCATGGCCGTATCCAAGGAGGATTAATATGAGATATTCAGGTCGCTCATGTACTGGATTACAATTCAGTATGATACATGGGTCGGGTAAACCAAGAGAGAGATTAAAATAGGGCCCTTTGCCAACACCACCAAATATGCTTATGAATATGATGTTGATGGACAGCTCCAAACAGTTTACCTCAATGAAAGATAATGTGGCGGTACAACTACGATCTGAAATGGAACCTCCATTTACTGAAACCCAAGTAACAGTGCGCGTCTGACACCCCTTCGCTATGACCTGCGAGAAAGAATCACTCGACTGGGTGATGTTCAATATCGGTTGGATGAAGATGGTTTCCTACGTCAAAGGGGCACGGAAATCTTTGAATATAGCTCCAAGGGGCTTCTAACTCGAGTTTACAGTAAAGGCAGTGGCTGGACAGTGATCTACCGTTATGACGGCCTGGGAAGGCGTGTTTCTAGCAAAACCAGTCTAGGACAGCACCTGCAGTTTTTTTATGCTGACTTAACTTATCCCACTAGGATTACTCATGTCTACAACCATTCGAGTTCAGAAATTACCTCCCTGTATTATGATCTCAAAGGACATCTTTTTGCCATGGAAATCAGCAGTGGGGATGAATTCTATATTGCATCGGATAACACAGGGAAACCACTGGCTGTGTTCAGTAGCAATGGGCTTATGCTGAAACAGATTCAGTACACTGCATATGGGGAAATCTATTTTGACTCTAATATTGACTTTCCACTGGTATTGGATTTCATGGTGGCCTGTATGACCCACTCACCAAATTAAATCCACTTTGGAGAAAGAGATTATGACATTTTGGCAGGACGGTGGACAACACCTGACAATAGAATCTGGAAAAGAATTGGGAAGGACCCAGCTCCTTTTAACTTGTACATGTTTAGGAATAACAACCCTGCAAGCAAAATCCATGACGTGAAAGATTACATCACAGATGTTAACAGCTGGCTGGTGACATTTGGTTTCCATCTGCACAATGCTATTCCTGGATTCCCTGTTCCCATTTGATTTAACAGAACCTTCTTACGAAACTTGTGAAAGAGTCAGAAGTGGGATGATATACCGCCCATCTTCGGAGTCCAGCAGCAAGTGGCGCGGCAGGCCAAGGCCTTCCTGTCGCTGGGGAAGATGGCCGAGGTGCAGGTGAGCCGGCGCCGGGCCGGCGGCGCGCAGTCCTGGCTGTGGTTCGCCACGGTCAAGTCGCTGATCGGCAAGGGCGTCATGCTGGCCGTCAGCCAGGGCCGCGTGCAGACCAACGTGCTCACATCGCCAACGAGGACTGCATCAAGGTGGCGGCCGTGCTCAACAAACGCCTTCTACCTGGAGAACCTGCACTTCACCATCGAGGGCAAGGACACGCACTACTTCATCAAGACCACCACGCCCGAGAGCGACCTAAGCACGCTGCGGTTGACCAGCGGCCGCAAGGCGCTGGAGAACGGCATCAACGTGACGGTGTCGCAGTCAACCACGGTGGTGAACGGCAGGACGCGCAGGTTCGCGGACGTGGAGATGCAGTTCGGCGCGCTGGCGCTGCACGTGCGCTACGGCATGACCCTGGACGAGGAGAAGGCGCGCATCCTGGAGCAGGCGCGGCAGCGCGCGCTCGCCCGGGCCTGGGCGCGCGAGCAGCAGCGCGTGCGCGACGGCGAGGAGGGCGCGCGCCTCTGGACGGAGGGCGAGAAGCGGCAGCTGCTGAGCGCCGGCAAGGTGCAGGGCTACGACGGGTACTACGTACTCTCGGTGGAGAAGTACCCCGAGCTGGCCGACAGCGCCAACAACATCCAGTTCCTGCGGCAGAGCGAGATCGGCAGGAGGTAA CGCCCGGGCCGCGCCCGCCGAGCCGCTCACGCCCTGCCCACATTGTCCTGTGGCACAACCCGAGTGGGACTCTCCAACGCCCAAGAGCCTTCCTCCCGGGGGAATGAGACTGCTGTTACGACCCACACCAACACCGCGAAAACAGGACCGCTTTTTTCCGAATGACCTTAAGGTGATCGGCTTTAACGAATAATGTTTAAAATATGAATAGCGCTGCACTCAGTCGGACTGAACGTAGCCAGAGGAAAAAAAAATCATCAAGGACAAAGGCCTCGACCTGTTGCGCTGGGCCGTCTGTTCCTTCTAGGCACTGTATTTAACTAACTTTAAAAAAAAAAAAAAAAAAG

[0280] The TEN-M3 NOV15a disclosed in this invention maps to chromosome4.

[0281] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 5307 of 5309 bases(99%) identical to a gb:GENBANK-ID:AB040888|acc:AB040888.1 mRNA fromHomo sapiens (Homo sapiens mRNA for KLAA1455 protein, partial cds).

[0282] A disclosed NOV15a polypeptide (SEQ ID NO:36) encoded by SEQ IDNO:35 has 2725 amino acid residues and is presented in Table 15B usingthe one-letter code. NOV15a seems to be a Type II (Ncyt Cexo) membraneprotein with an INTEGRAL Likelihood of −9.39 for Transmembrane 309-325(305-337). The SignalP, Psort and/or Hydropathy results predict thatNOV15a has no signal peptide and is likely to be localized in thenucleus with a certainty of 0.8000. In an alternative embodiment, NOV15ais likely to be localized to the plasma membrane with a certainty of0.7900, or to the microbody (peroxisome) with a certainty of 0.3424, orto the Golgi body with a certainty of 0.3000. TABLE 15B NOV15a proteinsequence (SEQ ID NO:36)MDVKERRPYCSLTKSRREKERRYTNSSADNEECRVPTQKSYSSSETLKAFDHDSSRLLYGNRVKDLVHREADEFTRQGQNFTLRQLGVCEPATRRGLAFCAEMGLPHRGYSISAGSDADTENEAVMSPEHAMRLWGRGVKSGRSSCLSSRSNSALTLTDTEHENKSDSENEQPASNQGQSTLQPLPPSHKQHSAQHHPSITSLNRNSLTNRRNQSPAPPAALPAELQTTPESVQLQDSWVLGSNVPLESRHFLFKTGTGTTPLFSTATPGYTMASGSVYSPPTRPLPRNTLSRSAFKFKKSSKYCSWKCTALCAVGVSVLLAILLSYFIAMHLFGLNWQLQQTENDTFENGKVNSDTMPTNTVSLPSGDNGKLGGFTQENNTIDSGELDIGRRAIQEIPPGIFWRSQLFIDQPQFLKFNISLQKDALIGVYGRKKLPPSHTQSSPQYDFVELLDGSRLIAREQRSLLETERAGRQARSVSLHEAGFIQYLDSGIWHLAFYNDGKNAEQVSFNTIVIESVVECPRNCHGNGECVSGTCHCFPGFLGPDCSRAACPVLCSGNGQYSKGRCLCFSGWKGTECDVPTTQCIDPQCGGRGICIMGSCACSSGYKGESCEEADCIDPGCSNHGVCIHGECHCSPGWGGSNCEILKTMCPDQCSGHGTYLQESGSCTCDPNWTGPDCSNEICSVDCGSHGVCMGGTCRCEEGWTGPACNQRACHPRCAEHGTCKDGKCECSQGWNGEHCTIAHYLDKIVKDKIGYKEGCPGLCNSNGRCTLDQNGGHCVCQPGWRGAGCDVAMETLCTDSKDNEGDGLIDCMDPDCCLQSSCQNQPYCRGLPDPQDIISQSLQSPSQQAAKSFYDRISFLIGSDSTHVIPGESPFNKSLASVIRGQVLTADGTPLIGVNVSFFHYPEYGYTITRQDGMFDLVANGGASLTLVFERSPFLTQYHTVWIPWNVFYVMDTLVMEKEENDIPSCDLSGFVRPNPIIVSSPLSTFFRSSPEDSPIIPETQVLHEETTIPGTDLKLSYLSSRAAGYKSVLKITMTQSIIPFNLMKVHLMVAVVGRLFQKWFPASPNLAYTFIWDKTDAYNQKVYGLSEAVVSVGYEYESCLDLTLWEKRTAILQGYELDASNMGGWTLDKHHVLDVQNGILYKGNGENQFISQQPPVVSSIMGNGRRRSISCPSCNGQADGNKLLAPVALACGIDGSLYVGDFNYVRRIFPSGNVTSVLELRNKDFRHSSNPAHRYYLATDPVTGDLYVSDTNTRRIYRPKSLTGAKDLTKNAEVVAGTGEQCLPFDEARCGDGGKAVEATLMSPKGMAVDKNGLIYFVDGTMIRKVDQNGIISTLLGSNDLTSARPLTCDTSMHISQVRLEWPTDLAINPMDNSIYVLDNNVVLQITENRQVRIAAGRPMHCQVPGVEYPVGKHAVQTTLESATAIAVSYSGVLYITETDEKKINRIRQVTTDGEISLVAGIPSECDCKNDANCDCYQSGDGYAKDAKLSAPSSLAASPDGTLYIADLGNIRIRAVSKNKPLLNSMNFYEVASPTDQELYIFDINGTHQYTVSLVTGDYLYNFSYSNDNDITAVTDSNGNTLRIRRDPNRMPVRVVSPDNQVIWLTIGTNGCLKGMTAQGLELVLFTYHGNSGLLATKSDETGWTTFFDYDSEGRLTNVTFPTGVVTNLHGDMDKAITVDIESSSREEDVSITSNLSSIDSFYTMVQDQLRNSYQIGYDGSLRIIYASGLDSHYQTEPHVLAGTANPTVAKRNMTLPGENGQNLVEWRFRKEQAQGKVNVFGRKLRVNGRNLLSVDFDRTTKTEKIYDDHRKFLLRIAYDTSGHPTLWLPSSKLMAVNVTYSSTGQIASIQRGTTSEKVDYDGQGRIVSRVFADGKTWSYTYLEKSMVLLLHSQRQYIFEYDMWDRLSAITMPSVARHTMQTIRSIGYYRNIYNPPESNASIITDYNEEGLLLQTAFLGTSRRVLFKYRRQTRLSEILYDSTRVSFTYDETAGVLKTVNLQSDGFICTIRYRQIGPLIDRQIFRFSEDGMVNARFDYSYDNSFRVTSMQGVINETPLPIDLYQFDDISGKVEQFGKFGVIYYDINQIISTAVMTYTKHFDAHGRIKEIQYEIFRSLMYWITIQYDNMGRVTKREIKIGPFANTTKYAYEYDVDGQLQTVYLNEKIMWRYNYDLNGNLHLLNPSNSARLTPLRYDLRDRITRLGDVQYRLDEDGFLRQRGTEIFEYSSKGLLTRVYSKGSGWTVIYRYDGLGRRVSSKTSLGQHLQFFYADLTYPTRITHVYNHSSSEITSLYYDLQGHLFAMEISSGDEFYIASDNTGTPLAVFSSNGLMLKQIQYTAYGEIYFDSNIDFQLVIGFHGGLYDPLTKLIHFGERDYDILAGRWTTPDIEIWKRIGKDPAPFNLYMFRNNNPASKIHDVKDYITDVNSWLVTFGFHLHNAIPGFPVPKFDLTEPSYELVKSQQWDDIPPIFGVQQQVARQAKAFLSLGKMAEVQVSRRRAGGAQSWLWFATVKSLIGKGVMLAVSQGRVQTNVLNIANEDCIKVAAVLNNAFYLENLHFTIEGKDTHYFIKTTTPESDLGTLRLTSGRKALENGINVTVSQSTTVVNGRTRRFADVEMQFGALALHVRYGMTLDEEKARILEQARQRALARAWAREQQRVRDGEEGARLWTEGEKRQLLSAGKVQGYDGYYVLSVEQYPELADSANNIQFLRQSEIGRR

[0283] The full amino acid sequence of the protein of the invention wasfound to have 2663 of 2725 amino acid residues (97%) identical to, and2696 of 2725 amino acid residues (98%) similar to, the 2715 amino acidresidue ptnr:SPTREMBL-ACC:Q9WTS6 protein from Mus musculus (Mouse)(TEN-M3).

[0284] The TEN-M3 disclosed in this invention is expressed in at leastthe following tissues: Brain, Cerebellum, Colon, Coronary Artery,Dermis, Heart, Hippocampus, Kidney, Lung, Lymph node, Mammarygland/Breast, Ovary, Parathyroid Gland, Pineal Gland, Placenta,Prostate, Smooth Muscle, Testis, Uterus. This information was derived bydetermining the tissue sources of the sequences that were included inthe invention including but not limited to SeqCalling sources, PublicEST sources, Literature sources, and/or RACE sources. Taqman expressionanalysis reveals that The TEN-M3 disclosed in this invention isexpressed by several brain regions and by brain and lung tumor derivedcell lines in TaqMan panel 1 and by kidney and lung tumors in panel 2.

[0285] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from cancer preferably in kidney andlung tumors The Potential Role(s) of TEN-M3-like protein and nucleicacid disclosed herein in Tumorgenesis is likely to be related to cellmigration and invasion conferring higher metastatic potential.Therapeutic targeting of of TEN-M3-like protein and nucleic aciddisclosed herein with a monoclonal antibody is anticipated to limit orblock the extent of tumor cell migration and invasion and tumormetastasis, preferably in melanomas tumors.

[0286] NOV15b

[0287] A disclosed NOV15b nucleic acid of 8645 nucleotides (alsoreferred to as CG55069-02) (SEQ ID NO:37) encoding a novel TEN-M3-likeprotein is shown in Table 15C. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 151-153 and endingwith a TAA codon at nucleotides 8314-8316. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined and the start and stop codons are in bold in Table15C. TABLE 15C NOV15b nucleotide sequenceTTTGGCCTCGGGCCAGAATTCGGCACGAGGGGTCTGGAGCTTGGAGGAGAAGTCTGAACT (SEQ IDNO:37) AAGGATAAACTAAAGAGAGGCCAATGAGACTTGAACCCTGAGCCTAAGTTGTCACCAGCAGGACTGATGTGCACACAGAAGGAATGAAGTATGGATGTGAAAGAACGCAGGCCTTACTGCTCCCTGACCAAGAGCAGACGAGAGAAGGAACGGCGCTACACAAATTCCTCCGCAGACAATGAGGAGTGCCGGGTACCCACACAGAAGTCCTACAGTTCCAGCGAGACATTGAAAGCTTTTGATCATGATTCCTCGCGGCTGCTTTACGGCAACAGAGTGAAGGATTTGGTTCACAGAGAAGCAGACGAGTTCACTAGACAAGGACAGAATTTTACCCTAAGGCAGTTAGGAGTTTGTGAACCAGCAACTCGAAGAGGACTGGCATTTTGTGCGGAAATGGGGCTCCCTCACAGAGGTTACTCTATCAGTGCAGGGTCAGATGCTGATACTGAAAATGAAGCAGTGATGTCCCCAGAGCATGCCATGAGACTTTGGGGCAGGGGGGTCAAATCAGGCCGCAGCTCCTGCCTGTCAAGTCGGTCCAACTCAGCCCTCACCCTGACAGATACGGAGCACGAAAACAAGTCCGACAGTGAGAATGAGCAACCTGCAAGCAATCAAGGCCAGTCTACCCTGCAGCCCTTGCCGCCTTCCCATAAGCAGCACTCTGCACAGCATCATCCATCCATCACTTCTCTCAACAGAAACTCCCTGACCAATAGAAGGAACCAGAGTCCGGCCCCGCCGGCTGCTTTGCCCGCCGAGCTGCAAACCACACCCGAGTCCGTCCAGCTGCAGGACAGCTGGGTCCTTGGCAGTAATGTACCACTGGAAAGCAGGCATTTCCTATTCAAAACAGGAACAGGTACAACGCCACTGTTCAGTACTGCAACCCCAGGATACACAATGGCATCTGGCTCTGTTTATTCACCACCTACTCGGCCACTACCTAGAAACACCCTATCAAGAAGTGCTTTTAAATTCAAGAAGTCTTCAAAGTACTGTAGCTGGAAATGCACTGCACTGTGTGCCGTAGGGGTCTCGGTGCTCCTGGCAATACTCCTGTCTTATTTTATAGCAATGCATCTCTTTGGCCTCAACTGGCAGCTACAGCAGACTGAAAATGACACATTTGAGAATGGAAAAGTGAATTCTGATACCATGCCAACAAACACTGTGTCATTACCTTCTGGAGACAATGGAAAATTAGGTGGATTTACGCAAGAAAATAACACCATAGATTCCGGAGAACTTGATATTGGCCGAAGAGCAATTCAAGAGATTCCTCCCGGGATCTTCTGGAGATCACAGCTCTTCATTGATCAGCCACAGTTTCTTAAATTCAATATCTCTCTTCAGAAGGATGCATTGATTGGAGTATATGGCCGGAAAGGCTTACCGCCTTCCCATACTCAGTATGACTTCGTGGAGCTCCTGGATGGCAGCAGGCTGATTGCCAGAGAGCAGCGGAGCCTGCTTGAGACGGAGAGAGCCGGGCGGCAGGCGAGATCCGTCAGCCTTCATGAGGCCGGCTTTATCCAGTACTTGGATTCTGGAATCTGGCATCTGGCTTTTTATAATGATGGGAAAAATGCAGAGCAGGTGTCTTTTAATACCATTGTTATAGAGTCTGTGGTGGAATGTCCCCGAAATTGCCATGGAAATGGAGAATGCGTTTCTGGAACTTGCCATTGTTTTCCAGGATTTCTGGGTCCGGATTGTTCAAGAGCCGCCTGTCCAGTGTTATGTAGTGGCAACGGGCAGTACTCCAAGGGCCGCTGCCTGTGTTTCAGCGGCTGGAAGGGCACCGAGTGTGATGTGCCGACTACCCAGTGTATTGACCCACAGTGTGGGGGTCGTGGGATTTGTATCATGGGCTCCTGTGCTTGCAGCTCAGGATACAAAGGAGAAAGTTGTGAAGAAGCTGACTGTATAGACCCTGGGTGTTCTAATCATGGTGTGTGTATCCACGGGGAATGTCACTGCAGTCCAGGATGGGGAGGTAGCAATTGTGAAATACTGAAGACCATGTGTCCAGACCAGTGCTCCGGCCACGGAACGTATCTTCAAGAAAGTGGCTCCTGCACGTGTGACCCTAACTGGACTGGCCCAGACTGCTCAAACGAAATATGTTCTGTGGACTGTGGCTCACACGGCGTTTGCATGGGGGGGACGTGTCGCTGTGAAGAAGGCTGGACGGGCCCAGCCTGTAATCAGAGAGCCTGCCACCCCCGCTGTGCCGAGCACGGGACCTGCAAGGATGGCAAGTGTGAATGCAGCCAGGGCTGGAATGGAGAGCACTGCACTATCGCTCACTATTTGGATAAGATAGTTAAAGACAAGATAGGATATAAAGAGGGTTGTCCTGGTCTGTGCAACAGCAATGGAAGATGTACCCTGGACCAAAATGGCGGACATTGTGTGTGCCAGCCTGGATGGAGAGGAGCAGGCTGTGACGTAGCCATGGAGACTCTTTGCACAGATAGCAAGGACAATGAAGGGGATGGACTCATTGACTGCATGGATCCCGATTGCTGCCTACAGAGTTCCTGCCAGAATCAGCCCTATTGTCGGGGACTGCCGGATCCTCAGGACATCATTAGCCAAAGCCTTCAATCGCCTTCTCAGCAAGCTGCCAAATCCTTTTATGATCGAATCAGTTTCCTTATAGGATCTGATAGCACCCATGTTATACCTGGAGAAAGTCCTTTCAATAAGAGCCTTGCATCTGTCATCAGAGGCCAAGTACTGACTGCTGATGGAACTCCACTTATTGGAGTAAATGTCTCGTTTTTCCATTACCCAGAATATGGATATACTATTACCCGCCAGGACGGAATGTTTGACTTGGTGGCAAATGGTGGGGCCTCTCTAACTTTGGTATTTGAACGATCCCCATTCCTCACTCAGTATCATACTGTGTGGATTCCATGGAATGTCTTTTATGTGATGGATACCCTAGTCATGGAGAAAGAAGAGAATGACATTCCCAGCTGTGATCTGAGTGGATTCGTGAGGCCAAATCCCATCATTGTGTCATCACCTTTATCCACCTTTTTCAGATCTTCTCCTGAAGACAGTCCCATCATTCCCGAAACACAGGTACTCCACGAGGAAACTACAATTCCAGGAACAGATTTGAAACTCTCCTACTTGAGTTCCAGAGCTGCAGGGTATAAGTCAGTTCTCAAGATCACCATGACCCAGTCTATTATTCCATTTAATTTAATGAAGGTTCATCTTATGGTAGCTGTAGTAGGAAGACTCTTCCAAAAGTGGTTTCCTGCCTCACCAAACTTGGCCTATACTTTCATATGGGATAAAACAGATGCATATAATCAGAAAGTCTATGGTCTATCTGAAGCTGTTGTGTCAGTTGGATATGAGTATGAGTCGTGTTTGGACCTGACTCTGTGGGAAAAGAGGACTGCCATTCTGCAGGGCTATGAATTGGATGCGTCCAACATGGGTGGCTGGACATTAGATAAACATCACGTGCTGGATGTACAGAACGGTATACTGTACAAGGGAAACGGGGAAAACCAGTTCATCTCCCAGCAGCCTCCAGTCGTGAGTAGCATCATGGGCAATGGGCGAAGGCGCAGCATTTCCTGCCCCAGTTGCAATGGTCAAGCTGATGGTAACAAGTTACTGGCCCCAGTGGCGCTAGCTTGTGGGATCGATGGCAGTCTGTACGTAGGCGATTTCAACTACGTGCGGCGGATATTCCCTTCTGGAAATGTAACAAGTGTCTTAGAACTAAGAAATAAAGATTTTAGACATAGCAGCAACCCAGCTCATAGATACTACCTTGCAACGGATCCAGTCACGGGAGATCTGTACGTTTCTGACACAAACACCCGCAGAATTTATCGCCCAAAGTCACTTACGGGGGCAAAAGACTTGACTAAAAATGCAGAAGTCGTCGCAGGGACAGGGGAGCAATGCCTTCCGTTTGACGAGGCGAGATGTGGGGATGGAGGGAAGGCCGTGGAAGCCACACTCATGAGTCCCAAAGGAATGGCAGTTGATAAGAATGGATTAATCTACTTTGTTGATGGAACCATGATTAGGAAAGTTGACCAAAATGGAATCATATCAACTCTTCTGGGCTCTAACGATTTGACTTCAGCCAGACCTTTAACTTGTGACACCAGCATGCACATCAGCCAGGTACGTCTGGAATGGCCCACTGACCTAGCCATTAACCCTATGGATAACTCCATTTATGTCCTGGATAATAATGTAGTTTTACAGATCACTGAAAATCGTCAAGTTCGCATTGCTGCTGGACGGCCCATGCACTGTCAGGTTCCCGGAGTGGAATATCCTGTGGGGAAGCACGCGGTGCAGACAACACTGGAATCAGCCACTGCCATTGCTGTGTCCTACAGTGGGGTCCTGTACATTACTGAAACTGATGAGAAGAAAATTAACCGGATAAGGCAGGTCACAACAGATGGAGAAATCTCCTTAGTGGCCGGAATACCTTCAGAGTGTGACTGCAAAAATGATGCCAACTGTGACTGTTACCAGAGTGGAGATGGCTACGCCAAGGATGCCAAACTCAGTGCCCCATCCTCCCTGGCTGCTTCTCCAGATGGTACACTGTATATTGCAGATCTAGGGAATATCCGGATCCGGGCTGTGTCAAAGAATAAGCCTTTACTTAACTCTATGAACTTCTATGAAGTTGCGTCTCCAACTGATCAAGAACTCTACATCTTTGACATCAATGGTACTCACCAATATACTGTAAGTTTAGTCACTGGTGATTACCTTTACAATTTTAGCTACAGCAATGACAATGATATTACTGCTGTGACAGACAGCAATGGCAACACCCTTAGAATTAGACGGGACCCAAATCGCATGCCAGTTCGAGTGGTGTCTCCTGATAACCAAGTGATATGGTTGACAATAGGAACAAATGGATGTTTGAAAGGCATGACTGCTCAAGGACTGGAATTAGTTTTGTTTACTTACCATGGCAATAGTGGCCTTTTAGCCACTAAAAGTGATGAAACTGGATGGACAACGTTTTTTGACTATGACAGTGAAGGTCGTCTGACAAATGTTACGTTTCCAACTGGAGTGGTCACAAACCTGCATGGGGACATGGACAAGGCTATCACAGTGGACATTGAGTCATCTAGCCGAGAAGAAGATGTCAGCATCACTTCAAATCTGTCCTCGATCGATTCTTTCTACACCATGGTTCAAGATCAGTTAAGAAACAGCTACCAGATTGGTTATGACGGCTCCCTCAGAATTATCTACGCCAGTGGCCTGGACTCACACTACCAAACAGAGCCGCACGTTCTGGCTGGCACCGCTAATCCGACGGTTGCCAAAAGAAACATGACTTTGCCTGGCGAGAACGGTCAAAACTTGGTGGAATGGAGATTCCGAAAAGAGCAAGCCCAAGGGAAAGTCAATGTCTTTGGCCGCAAGCTCAGGGTTAATGGCAGAAACCTCCTTTCAGTTGACTTTGATCGAACAACAAAGACAGAAAAGATCTATGACGACCACCGTAAATTTCTACTGAGGATCGCCTACGACACGTCTGGGCACCCGACTCTCTGGCTGCCAAGCAGCAAGCTGATGGCCGTCAATGTCACCTATTCATCCACAGGTCAAATTGCCAGCATCCAGCGAGGCACCACTAGCGAGAAAGTAGATTATGACGGACAGGGGAGGATCGTGTCTCGGGTCTTTGCTGATGGTAAAACATGGAGTTACACATATTTAGAAAAGTCCATGGTTCTTCTGCTTCATAGCCAGCGGCAGTACATCTTCGAATACGATATGTGGGACCGCCTGTCTGCCATCACCATGCCCAGTGTGGCTCGCCACACCATGCAGACCATCCGATCCATTGGCTACTACCGCAACATATACAACCCCCCGGAAAGCAACGCCTCCATCATCACGGACTACAACGAGGAAGGGCTGCTTCTACAAACAGCTTTCTTGGGTACAAGTCGGAGGGTCTTATTCAAATACAGAAGGCAGACTAGGCTCTCAGAAATTTTATATGATAGCACAAGAGTCAGTTTTACCTATGATGAAACAGCAGGAGTCCTAAAGACAGTAAACCTCCAGAGTGATGGTTTTATTTGCACCATTAGATACAGGCAAATTGGTCCCCTGATTGACAGGCAGATTTTCCGCTTTAGTGAAGATGGGATGGTAAATGCAAGATTTGACTATAGCTATGACAACAGCTTTCGAGTGACCAGCATGCAGGGTGTGATCAATGAAACGCCACTGCCTATTGATCTGTATCAGTTTGATGACATTTCTGGCAAAGTTGAGCAGTTTGGAAAGTTTGGAGTTATATATTATGATATTAACCAGATCATTTCTACAGCTGTAATGACCTATACGAAGCACTTTGATGCTCATGGCCGTATCAAGGAGATTCAATATGAGATATTCAGGTCGCTCATGTACTGGATTACAATTCAGTATGATAACATGGGTCGGGTAACCAAGAGAGAGATTAAAATAGGGCCCTTTGCCAACACCACCAAATATGCTTATGAATATGATGTTGATGGACAGCTCCAAACAGTTTACCTCAATGAAAAGATAATGTGGCGGTACAACTACGATCTGAATGGAAACCTCCATTTACTGAACCCAAGTAACAGTGCGCGTCTGACACCCCTTCGCTATGACCTGCGAGACAGAATCACTCGACTGGGTGATGTTCAATATCGGTTGGATGAAGATGGTTTCCTACGTCAAAGGGGCACGGAAATCTTTGAATATAGCTCCAAGGGGCTTCTAACTCGAGTTTACAGTAAAGGCAGTGGCTGGACAGTGATCTACCGTTATGACGGCCTGGGAAGGCGTGTTTCTAGCAAAACCAGTCTAGGACAGCACCTGCAGTTTTTTTATGCTGACTTAACTTATCCCACTAGGATTACTCATGTCTACAACCATTCGAGTTCAGAAATTACCTCCCTGTATTATGATCTCCAAGGACATCTTTTTGCCATGGAAATCAGCAGTGGGGATGAATTCTATATTGCATCGGATAACACAGGGACACCACTGGCTGTGTTCAGTAGCAATGGGCTTATGCTGAAACAGATTCAGTACACTGCATATGGGGAAATCTATTTTGACTCTAATATTGACTTTCAACTGGTAATTGGATTTCATGGTGGCCTGTATGACCCACTCACCAAATTAATCCACTTTGGAGAAAGAGATTATGACATTTTGGCAGGACGGTGGACAACACCTGACATAGAAATCTGGAAAAGAATTGGGAAGGACCCAGCTCCTTTTAACTTGTACATGTTTAGGAATAACAACCCTGCAAGCAAAATCCATGACGTGAAAGATTACATCACAGATGTTAACAGCTGGCTGGTGACATTTGGTTTCCATCTGCACAATGCTATTCCTGGATTCCCTGTTCCCAAATTTGATTTAACAGAACCTTCTTACGAACTTGTGAAGAGTCAGCAGTGGGATGATATACCGCCCATCTTCGGAGTCCAGCAGCAAGTGGCGCGGCAGGCCAAGGCCTTCCTGTCGCTGGGGAAGATGGCCGAGGTGCAGGTGAGCCGGCGCCGGGCCGGCGGCGCGCAGTCCTGGCTGTGGTTCGCCACGGTCAAGTCGCTGATCGGCAAGGGCGTCATGCTGGCCGTCAGCCAGGGCCGCGTGCAGACCAACGTGCTCAACATCGCCAACGAGGACTGCATCAAGGTGGCGGCCGTGCTCAACAACGCCTTCTACCTGGAGAACCTGCACTTCACCATCGAGGGCAAGGACACGCACTACTTCATCAAGACCACCACGCCCGAGAGCGACCTGGGCACGCTGCGGTTGACCAGCGGCCGCAAGGCGCTGGAGAACGGCATCAACGTGACGGTGTCGCAGTCCACCACGGTGGTGAACGGCAGGACGCGCAGGTTCGCGGACGTGGAGATGCAGTTCGGCGCGCTGGCGCTGCACGTGCGCTACGGCATGACCCTGGACGAGGAGAAGGCGCGCATCCTGGAGCAGGCGCGGCAGCGCGCGCTCGCCCGGGCCTGGGCGCGCGAGCAGCAGCGCGTGCGCGACGGCGAGGAGGGCGCGCGCCTCTGGACGGAGGGCGAGAAGCGGCAGCTGCTGAGCGCCGGCAAGGTGCAGGGCTACGACGGGTACTACGTACTCTCGGTGGAGCAGTACCCCGAGCTGGCCGACAGCGCCAACAACATCCAGTTCCTGCGGCAGAGCGAGATCGGCAGGAGGTAACGCCCGGGCCGCGCCCGCCGAGCCGCTCACGCCCTGCCCACATTGTCCTGTGGCACAACCCGAGTGGGACTCTCCAACGCCAAGAGCCTTCCTCCCGGGGGAATGAGACTGCTGTTACGACCCACACCCACCGCGAAAACAAGGACCGCTTTTTTCCGAATGACCTTAAAGGTGATCGGCTTTAACGAATATGTTTACATATGCATAGCGCTGCACTCAGTCGGACTGAACGTAGCCAGAGGAAAAAAAAATCATCAAGGACAAAGGCCTCGACCTGTTGCGCTGGGCCGTCTGTTCCTTCTAGGCACTGTATTTAACTAA CTTTA

[0288] The TEN-M3 NOV15b disclosed in this invention maps to chromosome4.

[0289] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 5395 of 6175 bases(87%) identical to a gb:GENBANK-ID:AB025412|acc:AB025412.1 mRNA from Musmusculus (Mus musculus mRNA for Ten-m3, complete cds).

[0290] A disclosed NOV15b polypeptide (SEQ ID NO:38) encoded by SEQ IDNO:37 has 2721 amino acid residues and is presented in Table 15D usingthe one-letter code. Although PSORT suggests that the TEN-M3-likeprotein may be localized nucleus, the protein of CuraGen Acc. No.CG55069-02 predicted here is similar to the tenascins family, somemembers of which are secreted or membrane protein. Therefore it islikely that this novel TEN-M3-like protein also shows similarlocalization. The hydropathy plot supports this conclusion. NOV15b seemsto be a Type II (Ncyt Cexo) membrane protein with an INTEGRAL Likelihoodof −9.39 for Transmembrane 309-325 (305-337). The SignalP, Psort and/orHydropathy results predict that NOV15b has no signal peptide and islikely to be localized in the nucleus with a certainty of 0.8000. In analternative embodiment, NOV15b is likely to be localized to the plasmamembrane with a certainty of 0.7900, or to the microbody (peroxisome)with a certainty of 0.3453, or to the Golgi body with a certainty of0.3000. TABLE 15D NOV15b protein sequenceMDVKERRPYCSLTKSRREKERRYTNSSADNEECRVPTQKSYSSSETLKAFDHDSSRLLYG (SEQ IDNO:38) NRVKDLVHREADEFTRQGQNFTLRQLGVCEPATRRGLAFCAEMGLPHRGYSISAGSDADTENEAVMSPEHAMRLWGRGVKSGRSSCLSSRSNSALTLTDTEHENKSDSENEQPASNQGQSTLQPLPPSHKQHSAQHHPSITSLNRNSLTNRRNQSPAPPAALPAELQTTPESVQLQDSWVLGSNVPLESRHFLFKTGTGTTPLFSTATPGYTMASGSVYSPPTRPLPRNTLSRSAFKFKKSSKYCSWKCTALCAVGVSVLLAILLSYFIAMHLFGLNWQLQQTENDTFENGKVNSDTMPTNTVSLPSGDNGKLGGFTQENNTIDSGELDIGRRAIQEIPPGIFWRSQLFIDQPQFLKFNISLQKDALIGVYGRKGLPPSHTQYDFVELLDGSRLIAREQRSLLETERAGRQARSVSLHEAGFIQYLDSGIWHLAFYNDGKNAEQVSFNTIVIESVVECPRNCHGNGECVSGTCHCFPGFLGPDCSRAACPVLCSGNGQYSKGRCLCFSGWKGTECDVPTTQCIDPQCGGRGICIMGSCACSSGYKGESCEEADCIDPGCSNHGVCIHGECHCSPGWGGSNCEILKTMCPDQCSGHGTYLQESGSCTCDPNWTGPDCSNEICSVDCGSHGVCMGGTCRCEEGWTGPACNQRACHPRCAEHGTCKDGKCECSQGWNGEHCTIAHYLDKIVKDKIGYKEGCPGLCNSNGRCTLDQNGGHCVCQPGWRGAGCDVAMETLCTDSKDNEGDGLIDCMDPDCCLQSSCQNQPYCRGLPDPQDIISQSLQSPSQQAAKSFYDRISFLIGSDSTHVIPGESPFNKSLASVIRGQVLTADGTPLIGVNVSFFHYPEYGYTITRQDGMFDLVANGGASLTLVFERSPFLTQYHTVWIPWNVFYVMDTLVMEKEENDIPSCDLSGFVRPNPIIVSSPLSTFFRSSPEDSPIIPETQVLHEETTIPGTDLKLSYLSSRAAGYKSVLKITMTQSIIPFNLMKVHLMVAVVGRLFQKWFPASPNLAYTFIWDKTDAYNQKVYGLSEAVVSVGYEYESCLDLTLWEKRTAILQGYELDASNMGGWTLDKHHVLDVQNGILYKGNGENQFISQQPPVVSSIMGNGRRRSISCPSCNGQADGNKLLAPVALACGIDGSLYVGDFNYVRRIFPSGNVTSVLELRNKDFRHSSNPAHRYYLATDPVTGDLYVSDTNTRRIYRPKSLTGAKDLTKNAEVVAGTGEQCLPFDEARCGDGGKAVEATLMSPKGMAVDKNGLIYFVDGTMIRKVDQNGIISTLLGSNDLTSARPLTCDTSMHISQVRLEWPTDLAINPMDNSIYVLDNNVVLQITENRQVRIAAGRPMHCQVPGVEYPVGKHAVQTTLESATAIAVSYSGVLYITETDEKKINRIRQVTTDGEISLVAGIPSECDCKNDANCDCYQSGDGYAKDAKLSAPSSLAASPDGTLYIADLGNIRIRAVSKNKPLLNSMNFYEVASPTDQELYIFDINGTHQYTVSLVTGDYLYNFSYSNDNDITAVTDSNGNTLRIRRDPNRMPVRVVSPDNQVIWLTIGTNGCLKGMTAQGLELVLFTYHGNSGLLATKSDETGWTTFFDYDSEGRLTNVTFPTGVVTNLHGDMDKAITVDIESSSREEDVSITSNLSSIDSFYTMVQDQLRNSYQIGYDGSLRIIYASGLDSHYQTEPHVLAGTANPTVAKRNMTLPGENGQNLVEWRFRKEQAQGKVNVFGRKLRVNGRNLLSVDFDRTTKTEKIYDDHRKFLLRIAYDTSGHPTLWLPSSKLMAVNVTYSSTGQIASIQRGTTSEKVDYDGQGRIVSRVFADGKTWSYTYLEKSMVLLLHSQRQYIFEYDMWDRLSAITMPSVARHTMQTIRSIGYYRNIYNPPESNASIITDYNEEGLLLQTAFLGTSRRVLFKYRRQTRLSEILYDSTRVSFTYDETAGVLKTVNLQSDGFICTIRYRQIGPLIDRQIFRFSEDGMVNARFDYSYDNSFRVTSMQGVINETPLPIDLYQFDDISGKVEQFGKFGVIYYDINQIISTAVMTYTKHFDAHGRIKEIQYEIFRSLMYWITIQYDNMGRVTKREIKIGPFANTTKYAYEYDVDGQLQTVYLNEKIMWRYNYDLNGNLHLLNPSNSARLTPLRYDLRDRITRLGDVQYRLDEDGFLRQRGTEIFEYSSKGLLTRVYSKGSGWTVIYRYDGLGRRVSSKTSLGQHLQFFYADLTYPTRITHVYNHSSSEITSLYYDLQGHLFAMEISSGDEFYIASDNTGTPLAVFSSNGLMLKQIQYTAYGEIYFDSNIDFQLVIGFHGGLYDPLTKLIHFGERDYDILAGRWTTPDIEIWKRIGKDPAPFNLYMFRNNNPASKIHDVKDYITDVNSWLVTFGFHLHNAIPGFPVPKFDLTEPSYELVKSQQWDDIPPIFGVQQQVARQAKAFLSLGKMAEVQVSRRRAGGAQSWLWFATVKSLIGKGVMLAVSQGRVQTNVLNIANEDCIKVAAVLNNAFYLENLHFTIEGKDTHYFIKTTTPESDLGTLRLTSGRKALENGINVTVSQSTTVVNGRTRRFADVEMQFGALALHVRYGMTLDEEKARILEQARQRALARAWAREQQRVRDGEEGARLWTEGEKRQLLSAGKVQGYDGYYVLSVEQYPELADSANNIQFLRQSEIGRR

[0291] The full amino acid sequence of the protein of the invention wasfound to have 2664 of 2721 amino acid residues (97%) identical to, and2697 of 2721 amino acid residues (99%) similar to, the 2715 amino acidresidue ptnr:SPTREMBL-ACC:Q9WTS6 protein from Mus musculus (Mouse)(TEN-M3).

[0292] The TEN-M3-like gene disclosed in this invention is expressed inat least the following tissues: adrenal gland, bone marrow,brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantianigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetalliver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland,pancreas, pituitary gland, placenta, prostate, salivary gland, skeletalmuscle, small intestine, spinal cord, spleen, stomach, testis, thyroid,trachea and uterus.

[0293] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: CNS disorders, neuronaldevelopmental disorders, heart diseases such as stroke, myocardialinfarction, ischemia, cancer, localized and systemic scleroderma,pleural inflammatory and fibrotic diseases as well as other diseases,disorders and conditions.

[0294] NOV15c

[0295] A disclosed NOV15c nucleic acid of 8473 nucleotides (alsoreferred to as CG55069-03) (SEQ ID NO:39) encoding a novel TEN-M3-likeprotein is shown in Table 15E. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 258-260 and endingwith a TAA codon at nucleotides 8142-8144. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined and the start and stop codons are in bold in Table15E. TABLE 15E NOV15c nucleotide sequenceTTGACAGAAAAAGGCAGTAAACGGGGAATCTCTTTTTTTGAATAAAGAAGAAGAAGAAAT (SEQ IDNO:39) AAAGTACCTGTCATCTTGACAAGTGGCGGAGCGGAGGAGTCAAGGATTATAAATGATCACAGCCAGGTCCAGCTCGCCCCGTGATTGGGCTCTCCCGCGATCTGCACCGGGGGAAGCGCATGAGAGGCCAATGAGACTTGAACCCTGAGCCTAAGTTGTCACCAGCAGGACTGATGTGCACACAGAAGGAATGAAGTATGGATGTGAAAGAACGCAGGCCTTACTGCTCCCTGACCAAGAGCAGACGAGAGAAGGAACGGCGCTACACAAATTCCTCCGCAGACAATGAGGAGTGCCGGGTACCCACACAGAAGTCCTACAGTTCCAGCGAGACATTGAAAGCTTTTGATCATGATTCCTCGCGGCTGCTTTACGGCAACAGAGTGAAGGATTTGGTTCACAGAGAAGCAGACGAGTTCACTAGACAAGAGCAACCTGCAAGCAATCAAGGCCAGTCTACCCTGCAGCCCTTGCCGCCTTCCCATAAGCAGCACTCTGCACAGCATCATCCATCCATCACTTCTCTCAACAGAAACTCCCTGACCAATAGAAGGAACCAGAGTCCGGCCCCGCCGGCTGCTTTGCCCGCCGAGCTGCAAACCACACCCGAGTCCGTCCAGCTGCAGGACAGCTGGGTCCTTGGCAGTAATGTACCACTGGAAAGCAGGCATTTCCTATTCAAAACAGGAACAGGTACAACGCCACTGTTCAGTACTGCAACCCCAGGATACACAATGGCATCTGGCTCTGTTTATTCACCACCTACTCGGCCACTACCTAGAAACACCCTATCAAGAAGTGCTTTTAAATTCAAGAAGTCTTCAAAGTACTGTAGCTGGAAATGCACTGCACTGTGTGCCGTAGGGGTCTCGGTGCTCCTGGCAATACTCCTGTCTTATTTTATAGCAATGCATCTCTTTGGCCTCAACTGGCAGCTACAGCAGACTGAAAATGACACATTTGAGAATGGAAAAGTGAATTCTGATACCATGCCAACAAACACTGTGTCATTACCTTCTGGAGACAATGGAAAATTAGGTGGATTTACGCAAGAAAATAACACCATAGATTCCGGAGAACTTGATATTGGCCGAAGAGCAATTCAAGAGATTCCTCCCGGGATCTTCTGGAGATCACAGCTCTTCATTGATCAGCCACAGTTTCTTAAATTCAATATCTCTCTTCAGAAGGATGCATTGATTGGAGTATATGGCCGGAAAGGCTTACCGCCTTCCCATACTCAGTATGACTTCGTGGAGCTCCTGGATGGCAGCAGGCTGATTGCCAGAGAGCAGCGGAGCCTGCTTGAGACGGAGAGAGCCGGGCGGCAGGCGAGATCCGTCAGCCTTCATGAGGCCGGCTTTATCCAGTACTTGGATTCTGGAATCTGGCATCTGGCTTTTTATAATGATGGGAAAAATGCAGAGCAGGTGTCTTTTAATACCATTGTTATAGAGTCTGTGGTGGAATGTCCCCGAAATTGCCATGGAAATGGAGAATGCGTTTCTGGAACTTGCCATTGTTTTCCAGGATTTCTGGGTCCGGATTGTTCAAGAGCCGCCTGTCCAGTGTTATGTAGTGGCAACGGGCAGTACTCCAAGGGCCGCTGCCTGTGTTTCAGCGGCTGGAAGGGCACCGAGTGTGATGTGCCGACTACCCAGTGTATTGACCCACAGTGTGGGGGTCGTGGGATTTGTATCATGGGCTCTTGTGCTTGCAACTCAGGATACAAAGGAAAAAGTTGTGAAGAAGCTGACTGTATAGACCCTGGGTGTTCTAATCATGGTGTGTGTATCCACGGGGAATGTCACTGCAGTCCAGGATGGGGAGGTAGCAATTGTGAAATACTGAAGACCATGTGTCCAGACCAGTGCTCCGGCCACGGAACGTATCTTCAAGAAAGTGGCTCCTGCACGTGTGACCCTAACTGGACTGGCCCAGACTGCTCAAACGAAATATGTTCTGTGGACTGTGGCTCACACGGCGTTTGCATGGGGGGGACGTGTCGCTGTGAAGAAGGCTGGACGGGCCCAGCCTGTAATCAGAGAGCCTGCCACCCCCGCTGTGCCGAGCACGGGACCTGCAAGGATGGCAAGTGTGAATGCAGCCAGGGCTGGAATGGAGAGCACTGCACTATCGCTCACTATTTGGATAAGATAGTTAAAGACAAGATAGGATATAAAGAGGGTTGTCCTGGTCTGTGCAACAGCAATGGAAGATGTACCCTGGACCAAAATGGCGGACATTGTGTGTGCCAGCCTGGATGGAGAGGAGCAGGCTGTGACGTAGCCATGGAGACTCTTTGCACAGATAGCAAGGACAATGAAGGGGATGGACTCATTGACTGCATGGATCCCGATTGCTGCCTACAGAGTTCCTGCCAGAATCAGCCCTATTGTCGGGGACTGCCGGATCCTCAGGACATCATTAGCCAAAGCCTTCAATCGCCTTCTCAGCAAGCTGCCAAATCCTTTTATGATCGAATCAGTTTCCTTATAGGATCTGATAGCACCCATGTTATACCTGGAGAAAGTCCTTTCAATAAGAGCCTTGCATCTGTCATCAGAGGCCAAGTACTGACTGCTGATGGAACTCCACTTATTGGAGTAAATGTCTCGTTTTTCCATTACCCAGAATATGGATATACTATTACCCGCCAGGACGGAATGTTTGACTTGGTGGCAAATGGTGGGGCCTCTCTAACTTTGGTATTTGAACGATCCCCATTCCTCACTCAGTATCATACTGTGTGGATTCCATGGAATGTCTTTTATGTGATGGATACCCTAGTCATGGAGAAAGAAGAGAATGACATTCCCAGCTGTGATCTGAGTGGATTCGTGAGGCCAAATCCCATCATTGTGTCATCACCTTTATCCACCTTTTTCAGATCTTCTCCTGAAGACAGTCCCATCATTCCCGAAACACAGGTACTCCACGAGGAAACTACAATTCCAGGAACAGATTTGAAACTCTCCTACTTGAGTTCCAGAGCTGCAGGGTATAAGTCAGTTCTCAAGATCACCATGACCCAGTCTATTATTCCATTTAATTTAATGAAGGTTCATCTTATGGTAGCTGTAGTAGGAAGACTCTTCCAAAAGTGGTTTCCTGCCTCACCAAACTTGGCCTATACTTTCATATGGGATAAAACAGATGCATATAATCAGAAAGTCTATGGTCTATCTGAAGCTGTTGTGTCAGTTGGATATGAGTATGAGTCGTGTTTGGACCTGACTCTGTGGGAAAAGAGGACTGCCATTCTGCAGGGCTATGAATTGGATGCGTCCAACATGGGTGGCTGGACATTAGATAAACATCACGTGCTGGATGTACAGAACGGTATACTGTACAAGGGAAACGGGGAAAACCAGTTCATCTCCCAGCAGCCTCCAGTCGTGAGTAGCATCATGGGCAATGGGCGAAGGCGCAGCATTTCCTGCCCCAGTTGCAATGGTCAAGCTGATGGTAACAAGTTACTGGCCCCAGTGGCGCTAGCTTGTGGGATCGATGGCAGTCTGTACGTAGGCGATTTCAACTACGTGCGGCGGATATTCCCTTCTGGAAATGTAACAAGTGTCTTAGAACTAAGAAATAAAGATTTTAGACATAGCAGCAACCCAGCTCATAGATACTACCTTGCAACGGATCCAGTCACGGGAGATCTGTACGTTTCTGACACAAACACCCGCAGAATTTATCGCCCAAAGTCACTTACGGGGGCAAAAGACTTGACTAAAAATGCAGAAGTCGTCGCAGGGACAGGGGAGCAATGCCTTCCGTTTGACGAGGCGAGATGTGGGGATGGAGGGAAGGCCGTGGAAGCCACACTCATGAGTCCCAAAGGAATGGCAGTTGATAAGAATGGATTAATCTACTTTGTTGATGGAACCATGATTAGGAAAGTTGACCAAAATGGAATCATATCAACTCTTCTGGGCTCTAACGATTTGACTTCAGCCAGACCTTTAACTTGTGACACCAGCATGCACATCAGCCAGGTACGTCTGGAATGGCCCACTGACCTAGCCATTAACCCTATGGATAACTCCATTTATGTCCTGGATAATAATGTAGTTTTACAGATCACTGAAAATCGTCAAGTTCGCATTGCTGCTGGACGGCCCATGCACTGTCAGGTTCCCGGAGTGGAATATCCTGTGGGGAAGCACGCGGTGCAGACAACACTGGAATCAGCCACTGCCATTGCTGTGTCCTACAGTGGGGTCCTGTACATTACTGAAACTGATGAGAAGAAAATTAACCGGATAAGGCAGGTCACAACAGATGGAGAAATCTCCTTAGTGGCCGGAATACCTTCAGAGTGTGACTGCAAAAATGATGCCAACTGTGACTGTTACCAGAGTGGAGATGGCTACGCCAAGGATGCCAAACTCAGTGCCCCATCCTCCCTGGCTGCTTCTCCAGATGGTACACTGTATATTGCAGATCTAGGGAATATCCGGATCCGGGCTGTGTCAAAGAATAAGCCTTTACTTAACTCTATGAACTTCTATGAAGTTGCGTCTCCAACTGATCAAGAACTCTACATCTTTGACATCAATGGTACTCACCAATATACTGTAAGTTTAGTCACTGGTGATTACCTTTACAATTTTAGCTACAGCAATGACAATGATATTACTGCTGTGACAGACAGCAATGGCAACACCCTTAGAATTAGACGGGACCCAAATCGCATGCCAGTTCGAGTGGTGTCTCCTGATAACCAAGTGATATGGTTGACAATAGGAACAAATGGATGTTTGAAAGGCATGACTGCTCAAGGACTGGAATTAGTTTTGTTTACTTACCATGGCAATAGTGGCCTTTTAGCCACTAAAAGTGATGAAACTGGATGGACAACGTTTTTTGACTATGACAGTGAAGGTCGTCTGACAAATGTTACGTTTCCAACTGGAGTGGTCACAAACCTGCATGGGGACATGGACAAGGCTATCACAGTGGACATTGAGTCATCTAGCCGAGAAGAAGATGTCAGCATCACTTCAAATCTGTCCTCGATCGATTCTTTCTACACCATGGTTCAAGATCAGTTAAGAAACAGCTACCAGATTGGTTATGACGGCTCCCTCAGAATTATCTACGCCAGTGGCCTGGACTCACACTACCAAACAGAGCCGCACGTTCTGGCTGGCACCGCTAATCCGACGGTTGCCAAAAGAAACATGACTTTGCCTGGCGAGAACGGTCAAAACTTGGTGGAATGGAGATTCCGAAAAGAGCAAGCCCAAGGGAAAGTCAATGTCTTTGGCCGCAAGCTCAGGGTTAATGGCAGAAACCTCCTTTCAGTTGACTTTGATCGAACAACAAAGACAGAAAAGATCTATGACGACCACCGTAAATTTCTACTGAGGATCGCCTACGACACGTCTGGGCACCCGACTCTCTGGCTGCCAAGCAGCAAGCTGATGGCCGTCAATGTCACCTATTCATCCACAGGTCAAATTGCCAGCATCCAGCGAGGCACCACTAGCGAGAAAGTAGATTATGACGGACAGGGGAGGATCGTGTCTCGGGTCTTTGCTGATGGTAAAACATGGAGTTACACATATTTAGAAAAGTCCATGGTTCTTCTGCTTCATAGCCAGCGGCAGTACATCTTCGAATACGATATGTGGGACCGCCTGTCTGCCATCACCATGCCCAGTGTGGCTCGCCACACCATGCAGACCATCCGATCCATTGGCTACTACCGCAACATATACAACCCCCCGGAAAGCAACGCCTCCATCATCACGGACTACAACGAGGAAGGGCTGCTTCTACAAACAGCTTTCTTGGGTACAAGTCGGAGGGTCTTATTCAAATACAGAAGGCAGACTAGGCTCTCAGAAATTTTATATGATAGCACAAGAGTCAGTTTTACCTATGATGAAACAGCAGGAGTCCTAAAGACAGTAAACCTCCAGAGTGATGGTTTTATTTGCACCATTAGATACAGGCAAATTGGTCCCCTGATTGACAGGCAGATTTTCCGCTTTAGTGAAGATGGGATGGTAAATGCAAGATTTGACTATAGCTATGACAACAGCTTTCGAGTGACCAGCATGCAGGGTGTGATCAATGAAACGCCACTGCCTATTGATCTGTATCAGTTTGATGACATTTCTGGCAAAGTTGAGCAGTTTGGAAAGTTTGGAGTTATATATTATGATATTAACCAGATCATTTCTACAGCTGTAATGACCTATACGAAGCACTTTGATGCTCATGGCCGTATCAAGGAGATTCAATATGAGATATTCAGGTCGCTCATGTACTGGATTACAATTCAGTATGATAACATGGGTCGGGTAACCAAGAGAGAGATTAAAATAGGGCCCTTTGCCAACACCACCAAATATGCTTATGAATATGATGTTGATGGACAGCTCCAAACAGTTTACCTCAATGAAAAGATAATGTGGCGGTACAACTACGATCTGAATGGAAACCTCCATTTACTGAACCCAAGTAACAGTGCGCGTCTGACACCCCTTCGCTATGACCTGCGAGACAGAATCACTCGACTGGGTGATGTTCAATATCGGTTGGATGAAGATGGTTTCCTACGTCAAAGGGGCACGGAAATCTTTGAATATAGCTCCAAGGGGCTTCTAACTCGAGTTTACAGTAAAGGCAGTGGCTGGACAGTGATCTACCGTTATGACGGCCTGGGAAGGCGTGTTTCTAGCAAAACCAGTCTAGGACAGCACCTGCAGTTTTTTTATGCTGACTTAACTTATCCCACTAGGATTACTCATGTCTACAACCATTCGAGTTCAGAAATTACCTCCCTGTATTATGATCTCCAAGGACATCTTTTTGCCATGGAAATCAGCAGTGGGGATGAATTCTATATTGCATCGGATAACACAGGGACACCACTGGCTGTGTTCAGTAGCAATGGGCTTATGCTGAAACAGATTCAGTACACTGCATATGGGGAAATCTATTTTGACTCTAATATTGACTTTCAACTGGTAATTGGATTTCATGGTGGCCTGTATGACCCACTCACCAAATTAATCCACTTTGGAGAAAGAGATTATGACATTTTGGCAGGACGGTGGACAACACCTGACATAGAAATCTGGAAAAGAATTGGGAAGGACCCAGCTCCTTTTAACTTGTACATGTTTAGGAATAACAACCCTGCAAGCAAAATCCATGACGTGAAAGATTACATCACAGATGTTAACAGCTGGCTGGTGACATTTGGTTTCCATCTGCACAATGCTATTCCTGGATTCCCTGTTCCCAAATTTGATTTAACAGAACCTTCTTACGAACTTGTGAAGAGTCAGCAGTGGGATGATATACCGCCCATCTTCGGAGTCCAGCAGCAAGTGGCGCGGCAGGCCAAGGCCTTCCTGTCGCTGGGGAAGATGGCCGAGGTGCAGGTGAGCCGGCGCCGGGCCGGCGGCGCGCAGTCCTGGCTGTGGTTCGCCACGGTCAAGTCGCTGATCGGCAAGGGCGTCATGCTGGCCGTCAGCCAGGGCCGCGTGCAGACCAACGTGCTCAACATCGCCAACGAGGACTGCATCAAGGTGGCGGCCGTGCTCAACAACGCCTTCTACCTGGAGAACCTGCACTTCACCATCGAGGGCAAGGACACGCACTACTTCATCAAGACCACCACGCCCGAGAGCGACCTGGGCACGCTGCGGTTGACCAGCGGCCGCAAGGCGCTGGAGAACGGCATCAACGTGACGGTGTCGCAGTCCACCACGGTGGTGAACGGCAGGACGCGCAGGTTCGCGGACGTGGAGATGCAGTTCGGCGCGCTGGCGCTGCACGTGCGCTACGGCATGACCCTGGACGAGGAGAAGGCGCGCATCCTGGAGCAGGCGCGGCAGCGCGCGCTCGCCCGGGCCTGGGCGCGCGAGCAGCAGCGCGTGCGCGACGGCGAGGAGGGCGCGCGCCTCTGGACGGAGGGCGAGAAGCGGCAGCTGCTGAGCGCCGGCAAGGTGCAGGGCTACGACGGGTACTACGTACTCTCGGTGGAGCAGTACCCCGAGCTGGCCGACAGCGCCAACAACATCCAGTTCCTGCGGCAGAGCGAGATCGGCAGGAGGTAACGCCCGGGCCGCGCCCGCCGAGCCGCTCACGCCCTGCCCACATTGTCCTGTGGCACAACCCGAGTGGGACTCTCCAACGCCCAAGAGCCTTCCTCCCGGGGGAATGAGACTGCTGTTACGACCCACACCCACACCGCGAAAACAAGGACCGCTTTTTTCCGAATGACCTTAAAGGTGATCGGCTTTAACGAATATGTTTACATATGCATAGCGCTGCACTCAGTCGGACTGAACGTAGCCAGAGGAAAAAAAAATCATCAAGGACAAAGGCCTCGACCTGTTGCGCTGGGCCGTCTGTTCCTTCTAGGCACTGTATTTAACTAACTTTA

[0296] The TEN-M3 NOV15c disclosed in this invention maps to chromosome4.

[0297] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 5395 of 6175 bases(87%) identical to a gb:GENBANK-ID:AB025412|acc:AB025412.1 mRNA from Musmusculus (Mus musculus mRNA for Ten-m3, complete cds).

[0298] A disclosed NOV15c polypeptide (SEQ ID NO:40) encoded by SEQ IDNO:39 has 2628 amino acid residues and is presented in Table 15F usingthe one-letter code. NOV15c seems to be a Type II (Ncyt Cexo) membraneprotein with an INTEGRAL Likelihood of −9.39 for Transmembrane 216-232(212-244). Although PSORT suggests that the TEN-M3-like protein may belocalized in the nucleus, the protein of CuraGen Acc. No. CG55069-03predicted here is similar to the membrane protein family, some membersof which are secreted or are membrane bound. Therefore it is likely thatthis novel TEN-M3-like protein shows similar localization. The SignalP,Psort and/or Hydropathy results predict that NOV15c has no signalpeptide and is likely to be localized in the nucleus with a certainty of0.8000. In an alternative embodiment, NOV15c is likely to be localizedto the plasma membrane with a certainty of 0.7900, or to the microbody(peroxisome) with a certainty of 0.3577, or to the Golgi body with acertainty of 0.3000. TABLE 15F NOV15c protein sequenceMDVKERRPYCSLTKSRREKERRYTNSSADNEECRVPTQKSYSSSETLKAFDHDSSRLLYG (SEQ IDNO:40) NRVKDLVHREADEFTRQEQPASNQGQSTLQPLPPSHKQHSAQHHPSITSLNRNSLTNRRNQSPAPPAALPAELQTTPESVQLQDSWVLGSNVPLESRHFLFKTGTGTTPLFSTATPGYTMASGSVYSPPTRPLPRNTLSRSAFKFKKSSKYCSWKCTALCAVGVSVLLAILLSYFIAMHLFGLNWQLQQTENDTFENGKVNSDTMPTNTVSLPSGDNGKLGGFTQENNTIDSGELDIGRRAIQEIPPGIFWRSQLFIDQPQFLKFNISLQKDALIGVYGRKGLPPSHTQYDFVELLDGSRLIAREQRSLLETERAGRQARSVSLHEAGFIQYLDSGIWHLAFYNDGKNAEQVSFNTIVIESVVECPRNCHGNGECVSGTCHCFPGFLGPDCSRAACPVLCSGNGQYSKGRCLCFSGWKGTECDVPTTQCIDPQCGGRGICIMGSCACNSGYKGKSCEEADCIDPGCSNHGVCIHGECHCSPGWGGSNCEILKTMCPDQCSGHGTYLQESGSCTCDPNWTGPDCSNEICSVDCGSHGVCMGGTCRCEEGWTGPACNQRACHPRCAEHGTCKDGKCECSQGWNGEHCTIAHYLDKIVKDKIGYKEGCPGLCNSNGRCTLDQNGGHCVCQPGWRGAGCDVAMETLCTDSKDNEGDGLIDCMDPDCCLQSSCQNQPYCRGLPDPQDIISQSLQSPSQQAAKSFYDRISFLIGSDSTHVIPGESPFNKSLASVIRGQVLTADGTPLIGVNVSFFHYPEYGYTITRQDGMFDLVANGGASLTLVFERSPFLTQYHTVWIPWNVFYVMDTLVMEKEENDIPSCDLSGFVRPNPIIVSSPLSTFFRSSPEDSPIIPETQVLHEETTIPGTDLKLSYLSSRAAGYKSVLKITMTQSIIPFNLMKVHLMVAVVGRLFQKWFPASPNLAYTFIWDKTDAYNQKVYGLSEAVVSVGYEYESCLDLTLWEKRTAILQGYELDASNMGGWTLDKHHVLDVQNGILYKGNGENQFISQQPPVVSSIMGNGRRRSISCPSCNGQADGNKLLAPVALACGIDGSLYVGDFNYVRRIFPSGNVTSVLELRNKDFRHSSNPAHRYYLATDPVTGDLYVSDTNTRRIYRPKSLTGAKDLTKNAEVVAGTGEQCLPFDEARCGDGGKAVEATLMSPKGMAVDKNGLIYFVDGTMIRKVDQNGIISTLLGSNDLTSARPLTCDTSMHISQVRLEWPTDLAINPMDNSIYVLDNNVVLQITENRQVRIAAGRPMHCQVPGVEYPVGKHAVQTTLESATAIAVSYSGVLYITETDEKKINRIRQVTTDGEISLVAGIPSECDCKNDANCDCYQSGDGYAKDAKLSAPSSLAASPDGTLYIADLGNIRIRAVSKNKPLLNSMNFYEVASPTDQELYIFDINGTHQYTVSLVTGDYLYNFSYSNDNDITAVTDSNGNTLRIRRDPNRMPVRVVSPDNQVIWLTIGTNGCLKGMTAQGLELVLFTYHGNSGLLATKSDETGWTTFFDYDSEGRLTNVTFPTGVVTNLHGDMDKAITVDIESSSREEDVSITSNLSSIDSFYTMVQDQLRNSYQIGYDGSLRIIYASGLDSHYQTEPHVLAGTANPTVAKRNMTLPGENGQNLVEWRFRKEQAQGKVNVFGRKLRVNGRNLLSVDFDRTTKTEKIYDDHRKFLLRIAYDTSGHPTLWLPSSKLMAVNVTYSSTGQIASIQRGTTSEKVDYDGQGRIVSRVFADGKTWSYTYLEKSMVLLLHSQRQYIFEYDMWDRLSAITMPSVARHTMQTIRSIGYYRNIYNPPESNASIITDYNEEGLLLQTAFLGTSRRVLFKYRRQTRLSEILYDSTRVSFTYDETAGVLKTVNLQSDGFICTIRYRQIGPLIDRQIFRFSEDGMVNARFDYSYDNSFRVTSMQGVINETPLPIDLYQFDDISGKVEQFGKFGVIYYDINQIISTAVMTYTKHFDAHGRIKEIQYEIFRSLMYWITIQYDNMGRVTKREIKIGPFANTTKYAYEYDVDGQLQTVYLNEKIMWRYNYDLNGNLHLLNPSNSARLTPLRYDLRDRITRLGDVQYRLDEDGFLRQRGTEIFEYSSKGLLTRVYSKGSGWTVIYRYDGLGRRVSSKTSLGQHLQFFYADLTYPTRITHVYNHSSSEITSLYYDLQGHLFAMEISSGDEFYIASDNTGTPLAVFSSNGLMLKQIQYTAYGEIYFDSNIDFQLVIGFHGGLYDPLTKLIHFGERDYDILAGRWTTPDIEIWKRIGKDPAPFNLYMFRNNNPASKIHDVKDYITDVNSWLVTFGFHLHNAIPGFPVPKFDLTEPSYELVKSQQWDDIPPIFGVQQQVARQAKAFLSLGKMAEVQVSRRRAGGAQSWLWFATVKSLIGKGVMLAVSQGRVQTNVLNIANEDCIKVAAVLNNAFYLENLHFTIEGKDTHYFIKTTTPESDLGTLRLTSGRKALENGINVTVSQSTTVVNGRTRRFADVEMQFGALALHVRYGMTLDEEKARILEQARQRALARAWAREQQRVRDGEEGARLWTEGEKRQLLSAGKVQGYDGYYVLSVEQYPELADSANNIQFLRQSEIGRR

[0299] The full amino acid sequence of the protein of the invention wasfound to have 2505 of 2575 amino acid residues (97%) identical to, and2537 of 2575 amino acid residues (98%) similar to, the 2715 amino acidresidue ptnr:SPTREMBL-ACC:Q9WTS6 protein from Mus musculus (Mouse)(TEN-M3).

[0300] The TEN-M3-like gene disclosed in this invention is expressed inat least the following tissues: adrenal gland, bone marrow,brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantianigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetalliver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland,pancreas, pituitary gland, placenta, prostate, salivary gland, skeletalmuscle, small intestine, spinal cord, spleen, stomach, testis, thyroid,trachea and uterus.

[0301] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: CNS disorders, neuronaldevelopmental disorders, heart diseases such as stroke, myocardialinfarction, ischemia, cancer, localized and systemic scleroderma,pleural inflammatory and fibrotic diseases as well as other diseases,disorders and conditions.

[0302] NOV15d

[0303] A disclosed NOV15d nucleic acid of 8487 nucleotides (alsoreferred to as CG55069-08) (SEQ ID NO:41) encoding a novel TEN-M3-likeprotein is shown in Table 15G. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 299-301 and endingwith a TAA codon at nucleotides 8138-8140. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined and the start and stop codons are in bold in Table15G. TABLE 15G NOV15d nucleotide sequence (SEQ ID NO:41)ACTCACTATAGGGCTCGAGCGGCCGCCCGGGCAGGTCCCATTTGACAGAAAAAGGCAGTAAACGGGGAATCTCTTTTTTTGAATAAAGAAGAAGAAGAAATAAAGTACCTGTCATCTTGACAAGTGGCGGAGCGGAGGAGTCAAGGATTATAAATGATCACAGCCAGGTCCAGCTCGCCCCGTGATTGGGCTCTCCCGCGATCTGCACCGGGGGAAGCGCATGAGAGGCCAATGAGACTTGAACCCTGAGCCTAAGTTGTCACCAGCAGGACTGATGTGCACACAGAAGGAATGAAGTATGGATGTGAAAGAACGCAGGCCTTACTGCTCCCTGACCAAGAGCAGACGAGAGAAGGAACGGCGCTACACAAATTCCTCCGCAGACAATGAGGAGTGCCGGGTACCCACACAGAAGTCCTACAGTTCCAGCGAGACATTGAAAGCTTTTGATCATGATTCCTCGCGGCTGCTTTACGGCAACAGAGTGAAGGATTTGGTTCACAGAGAAGCAGACGAGTTCACTAGACAAGAGCAACCTGCAAGCAATCAAGGCCAGTCTACCCTGCAGCCCTTGCCGCCTTCCCATAAGCAGCACTCTGCACAGCATCATCCATCCATCACTTCTCTCAACAGAAACTCCCTGACCAATAGAAGGAACCAGAGTCCGGCCCCGCCGGCTGCTTTGCCCGCCGAGCTGCAAACCACACCCGAGTCCGTCCAGCTGCAGGACAGCTGGGTCCTTGGCAGTAATGTACCACTGGAAAGCAGGCATTTCCTATTCAAAACAGGAACAGGTACAACGCCACTGTTCAGTACTGCAACCCCAGGATACACAATGGCATCTGGCTCTGTTTATTCACCACCTACTCGGCCACTACCTAGAAACACCCTATCAAGAAGTGCTTTTAAATTCAAGAAGTCTTCAAAGTACTGTAGCTGGAAATGCACTGCACTGTGTGCCGTAGGGGTCTCGGTGCTCCTGGCAATACTCCTGTCTTATTTTATAGCAATGCATCTCTTTGGCCTCAACTGGCAGCTACAGCAGACTGAAAATGACACATTTGAGAATGGAAAAGTGAATTCTGATACCATGCCAACAAACACTGTGTCATTACCTTCTGGAGACAATGGAAAATTAGGTGGATTTACGCAAGAAAATAACACCATAGATTCCGGAGAACTTGATATTGGCCGAAGAGCAATTCAAGAGATTCCTCCCGGGATCTTCTGGAGATCACAGCTCTTCATTGATCAGCCACAGTTTCTTAAATTCAATATCTCTCTTCAGAAGGATGCATTGATTGGAGTATATGGCCGGAAAGGCTTACCGCCTTCCCATACTCAGTATGACTTCGTGGAGCTCCTGGATGGCAGCAGGCTGATTGCCAGAGAGCAGCGGAGCCTGCTTGAGACGGAGAGAGCCGGGCGGCAGGCGAGATCCGTCAGCCTTCATGAGGCCGGCTTTATCCAGTACTTGGATTCTGGAATCTGGCATCTGGCTTTTTATAATGATGGGAAAAATGCAGAGCAGGTGTCTTTTAATACCATTGTTATAGAGTCTGTGGTGGAATGTCCCCGAAATTGCCATGGAAATGGAGAATGCGTTTCTGGAACTTGCCATTGTTTTCCAGGATTTCTGGGTCCGGATTGTTCAAGAGCCGCCTGTCCAGTGTTATGTAGTGGCAACGGGCAGTACTCCAAGGGCCGCTGCCTGTGTTTCAGCGGCTGGAAGGGCACCGAGTGTGATGTGCCGACTACCCAGTGTATTGACCCACAGTGTGGGGGTCGTGGGATTTGTATCATGGGCTCCTGTGCTTGCAACTCAGGATACAAAGGAGAAAGTTGTGAAGAAGCTGACTGTATAGACCCTGGGTGTTCTAATCATGGTGTGTGTATCCACGGGGAATGTCACTGCAGTCCAGGATGGGGAGGTAGCAATTGTGAAATACTGAAGACCATGTGTCCAGACCAGTGCTCCGGCCACGGAACGTATCTTCAAGAAAGTGGCTCCTGCACGTGTGACCCTAACTGGACTGGCCCAGACTGCTCAAACGAAATATGTTCTGTGGACTGTGGCTCACACGGCGTTTGCATGGGGGGGACGTGTCGCTGTGAAGAAGGCTGGACGGGCCCAACCTGTAATCAGAGAGCCTGCCACCCCCGCTGTGCCGAGCACGGGACCTGCAAGGATGGCAAGTGTGAATGCAGCCATGGCTGGAATGGAGAGCACTGCACTATCGAGGGTTGTCCTGGTCTGTGCAACAGCAATGGAAGATGTACCCTGGACCAAAATGGCTGGCATTGTGTGTGCCAGCCTGGATGGAGAGGAGCAGGCTGTGACGTAGCCATGGAGACTCTTTGCACAGATAGCAAGGACAATGAAGGAGATGGACTCATTGACTGCATGGATCCCGATTGCTGCCTACAGAGTTCCTGCCAGAATCAGCCCTATTGTCGGGGACTGCCGGATCCTCAGGACATCATTAGCCAAAGCCTTCAATCGCCTTCTCAGCAAGCTGCCAAATCCTTTTATGATCGAATCAGTTTCCTTATAGGATCTGATAGCACCCATGTTATACCTGGAGAAAGTCCTTTCAATAAGAGCCTTGCATCTGTCATCAGAGGCCAAGTACTGACTGCTGATGGAACTCCACTTATTGGAGTAAATGTCTCGTTTTTCCATTACCCAGAATATGGATATACTATTACCCGCCAGGACGGAATGTTTGACTTGGTGGCAAATGGTGGGGCCTCTCTAACTTTGGTATTTGAACGATCCCCATTCCTCACTCAGTATCATACTGTGTGGATTCCATGGAATGTCTTTTATGTGATGGATACCCTAGTCATGGAGAAAGAAGAGAATGACATTCCCAGCTGTGATCTGAGTGGATTCGTGAGGCCAAATCCCATCATTGTGTCATCACCTTTATCCACCTTTTTCAGATCTTCTCCTGAAGACAGTCCCATCATTCCCGAAACACAGGTACTCCACGAGGAAACTACAATTCCAGGAACAGATTTGAAACTCTCCTACTTGAGTTCCAGAGCTGCAGGGTATAAGTCAGTTCTCAAGATCACCATGACCCAGTCTATTATTCCATTTAATTTAATGAAGGTTCATCTTATGGTAGCTGTAGTAGGAAGACTCTTCCAAAAGTGGTTTCCTGCCTCACCAAACTTGGCCTATACTTTCATATGGGATAAAACAGATGCATATAATCAGAAAGTCTATGGTCTATCTGAAGCTGTTGTGTCAGTTGGATATGAGTATGAGTCGTGTTTGGACCTGACTCTGTGGGAAAAGAGGACTGCCATTCTGCAGGGCTATGAATTGGATGCGTCCAACATGGGTGGCTGGACATTAGATAAACATCACGTGCTGGATGTACAGAACGGTATACTGTACAAGGGAAACGGGGAAAACCAGTTCATCTCCCAGCAGCCTCCAGTCGTGAGTAGCATCATGGGCAATGGGCGAAGGCGCAGCATTTCCTGCCCCAGTTGCAATGGTCAAGCTGATGGTAACAAGTTACTGGCCCCAGTGGCGCTAGCTTGTGGGATCGATGGCAGTCTGTACGTAGGCGATTTCAACTACGTGCGGCGGATATTCCCTTCTGGAAATGTAACAAGTGTCTTAGAACTAAGAAATAAAGATTTTAGACATAGCAGCAACCCAGCTCATAGATACTACCTTGCAACGGATCCAGTCACGGGAGATCTGTACGTTTCTGACACAAACACCCGCAGAATTTATCGCCCAAAGTCACTTACGGGGGCAAAAGACTTGACTAAAAATGCAGAAGTCGTCGCAGGGACAGGGGAGCAATGCCTTCCGTTTGACGAGGCGAGATGTGGGGATGGAGGGAAGGCCGTGGAAGCCACACTCATGAGTCCCAAAGGAATGGCAGTTGATAAGAATGGATTAATCTACTTTGTTGATGGAACCATGATTAGGAAAGTTGACCAAAATGGAATCATATCAACTCTTCTGGGCTCTAACGATTTGACTTCAGCCAGACCTTTAACTTGTGACACCAGCATGCACATCAGCCAGGTACGTCTGGAATGGCCCACTGACCTAGCCATTAACCCTATGGATAACTCCATTTATGTCCTGGATAATAATGTAGTTTTACAGATCACTGAAAATCGTCAAGTTCGCATTGCTGCTGGACGGCCCATGCACTGTCAGGTTCCCGGAGTGGAATATCCTGTGGGGAAGCACGCGGTGCAGACAACACTGGAATCAGCCACTGCCATTGCTGTGTCCTACAGTGGGGTCCTGTACATTACTGAAACTGATGAGAAGAAAATTAACCGGATAAGGCAGGTCACAACAGATGGAGAAATCTCCTTAGTGGCCGGAATACCTTCAGAGTGTGACTGCAAAAATGATGCCAACTGTGACTGTTACCAGAGTGGAGATGGCTACGCCAAGGATGCCAAACTCAGTGCCCCATCCTCCCTGGCTGCTTCTCCAGATGGTACACTGTATATTGCAGATCTAGGGAATATCCGGATCCGGGCTGTGTCAAAGAATAAGCCTTTACTTAACTCTATGAACTTCTATGAAGTTGCGTCTCCAACTGATCAAGAACTCTACATCTTTGACATCAATGGTACTCACCAATATACTGTAAGTTTAGTCACTGGTGATTACCTTTACAATTTTAGCTACAGCAATGACAATGATATTACTGCTGTGACAGACAGCAATGGCAACACCCTTAGAATTAGACGGGACCCAAATCGCATGCCAGTTCGAGTGGTGTCTCCTGATAACCAAGTGATATGGTTGACAATAGGAACAAATGGATGTTTGAAAGGCATGACTGCTCAAGGACTGGAATTAGTTTTGTTTACTTACCATGGCAATAGTGGCCTTTTAGCCACTAAAAGTGATGAAACTGGATGGACAACGTTTTTTGACTATGACAGTGAAGGTCGTCTGACAAATGTTACGTTTCCAACTGGAGTGGTCACAAACCTGCATGGGGACATGGACAAGGCTATCACAGTGGACATTGAGTCATCTAGCCGAGAAGAAGATGTCAGCATCACTTCAAATCTGTCCTCGATCGATTCTTTCTACACCATGGTTCAAGATCAGTTAAGAAACAGCTACCAGATTGGTTATGACGGCTCCCTCAGAATTATCTACGCCAGTGGCCTGGACTCACACTACCAAACAGAGCCGCACGTTCTGGCTGGCACCGCTAATCCGACGGTTGCCAAAAGAAACATGACTTTGCCTGGCGAGAACGGTCAAAACTTGGTGGAATGGAGATTCCGAAAAGAGCAAGCCCAAGGGAAAGTCAATGTCTTTGGCCGCAAGCTCAGGGTTAATGGCAGAAACCTCCTTTCAGTTGACTTTGATCGAACAACAAAGACAGAAAAGATCTATGACGACCACCGTAAATTTCTACTGAGGATCGCCTACGACACGTCTGGGCACCCGACTCTCTGGCTGCCAAGCAGCAAGCTGATGGCCGTCAATGTCACCTATTCATCCACAGGTCAAATTGCCAGCATCCAGCGAGGCACCACTAGCGAGAAAGTAGATTATGACGGACAGGGGAGGATCGTGTCTCGGGTCTTTGCTGATGGTAAAACATGGAGTTACACATATTTAGAAAAGTCCATGGTTCTTCTGCTTCATAGCCAGCGGCAGTACATCTTCGAATACGATATGTGGGACCGCCTGTCTGCCATCACCATGCCCAGTGTGGCTCGCCACACCATGCAGACCATCCGATCCATTGGCTACTACCGCAACATATACAACCCCCCGGAAAGCAACGCCTCCATCATCACGGACTACAACGAGGAAGGGCTGCTTCTACAAACAGCTTTCTTGGGTACAAGTCGGAGGGTCTTATTCAAATACAGAAGGCAGACTAGGCTCTCAGAAATTTTATATGATAGCACAAGAGTCAGTTTTACCTATGATGAAACAGCAGGAGTCCTAAAGACAGTAAACCTCCAGAGTGATGGTTTTATTTGCACCATTAGATACAGGCAAATTGGTCCCCTGATTGACAGGCAGATTTTCCGCTTTAGTGAAGATGGGATGGTAAATGCAAGATTTGACTATAGCTATGACAACAGCTTTCGAGTGACCAGCATGCAGGGTGTGATCAATGAAACGCCACTGCCTATTGATCTGTATCAGTTTGATGACATTTCTGGCAAAGTTGAGCAGTTTGGAAAGTTTGGAGTTATATATTATGATATTAACCAGATCATTTCTACAGCTGTAATGACCTATACGAAGCACTTTGATGCTCATGGCCGTATCAAGGAGATTCAATATGAGATATTCAGGTCGCTCATGTACTGGATTACAATTCAGTATGATAACATGGGTCGGGTAACCAAGAGAGAGATTAAAATAGGGCCCTTTGCCAACACCACCAAATATGCTTATGAATATGATGTTGATGGACAGCTCCAAACAGTTTACCTCAATGAAAAGATAATGTGGCGGTACAACTACGATCTGAATGGAAACCTCCATTTACTGAACCCAAGTAACAGTGCGCGTCTGACACCCCTTCGCTATGACCTGCGAGACAGAATCACTCGACTGGGTGATGTTCAATATCGGTTGGATGAAGATGGTTTCCTACGTCAAAGGGGCACGGAAATCTTTGAATATAGCTCCAAGGGGCTTCTAACTCGAGTTTACAGTAAAGGCAGTGGCTGGACAGTGATCTACCGTTATGACGGCCTGGGAAGGCGTGTTTCTAGCAAAACCAGTCTAGGACAGCACCTGCAGTTTTTTTATGCTGACTTAACTTATCCCACTAGGATTACTCATGTCTACAACCATTCGAGTTCAGAAATTACCTCCCTGTATTATGATCTCCAAGGACATCTTTTTGCCATGGAAATCAGCAGTGGGGATGAATTCTATATTGCATCGGATAACACAGGGACACCACTGGCTGTGTTCAGTAGCAATGGGCTTATGCTGAAACAGATTCAGTACACTGCATATGGGGAAATCTATTTTGACTCTAATATTGACTTTCAACTGGTAATTGGATTTCATGGTGGCCTGTATGACCCACTCACCAAATTAATCCACTTTGGAGAAAGAGATTATGACATTTTGGCAGGACGGTGGACAACACCTGACATAGAAATCTGGAAAAGAATTGGGAAGGACCCAGCTCCTTTTAACTTGTACATGTTTAGGAATAACAACCCTGCAAGCAAAATCCATGACGTGAAAGATTACATCACAGATGTTAACAGCTGGCTGGTGACATTTGGTTTCCATCTGCACAATGCTATTCCTGGATTCCCTGTTCCCAAATTTGATTTAACAGAACCTTCTTACGAACTTGTGAAGAGTCAGCAGTGGGATGATATACCGCCCATCTTCGGAGTCCAGCAGCAAGTGGCGCGGCAGGCCAAGGCCTTCCTGTCGCTGGGGAAGATGGCCGAGGTGCAGGTGAGCCGGCGCCGGGCCGGCGGCGCGCAGTCCTGGCTGTGGTTCGCCACGGTCAAGTCGCTGATCGGCAAGGGCGTCATGCTGGCCGTCAGCCAGGGCCGCGTGCAGACCAACGTGCTCAACATCGCCAACGAGGACTGCATCAAGGTGGCGGCCGTGCTCAACAACGCCTTCTACCTGGAGAACCTGCACTTCACCATCGAGGGCAAGGACACGCACTACTTCATCAAGACCACCACGCCCGAGAGCGACCTGGGCACGCTGCGGTTGACCAGCGGCCGCAAGGCGCTGGAGAACGGCATCAACGTGACGGTGTCGCAGTCCACCACGGTGGTGAACGGCAGGACGCGCAGGTTCGCGGACGTGGAGATGCAGTTCGGCGCGCTGGCGCTGCACGTGCGCTACGGCATGACCCTGGACGAGGAGAAGGCGCGCATCCTGGAGCAGGCGCGGCAGCGCGCGCTCGCCCGGGCCTGGGCGCGCGAGCAGCAGCGCGTGCGCGACGGCGAGGAGGGCGCGCGCCTCTGGACGGAGGGCGAGAAGCGGCAGCTGCTGAGCGCCGGCAAGGTGCAGGGCTACGACGGGTACTACGTACTCTCGGTGGAGCAGTACCCCGAGCTGGCCGACAGCGCCAACAACATCCAGTTCCTGCGGCAGAGCGAGATCGGCAGGAGGTAACGCCCGGGCCGCGCCCGCCGAGCCGCTCACGCCCTGCCCACATTGTCCTGTGGCACAACCCGAGTGGGACTCTCCAACGCCCAAGAGCCTTCCTCCCGGGGGAATGAGACTGCTGTTACGACCCACACCCACACCGCGAAAACAAGGACCGCTTTTTTCCGAATGACCTTAAAGGTGATCGGCTTTAACGAATATGTTTACATATGCATAGCGCTGCACTCAGTCGGACTGAACGTAGCCAGAGGAAAAAAAAATCATCAAGGACAAAGGCCTCGACCTGTTGCGCTGGGCCGTCTGTTCCTTCTAGGCACTGTATTTAACTAACTTTAAAAAAAAAAAAAAAAAAG

[0304] The TEN-M3 NOV15d disclosed in this invention maps to chromosome4.

[0305] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 5307 of 5309 bases(99%) identical to a gb:GENBANK-ID:AB040888|acc:AB040888.1 mRNA fromHomo sapiens (Homo sapiens mRNA for KIAA1455 protein, partial cds).

[0306] A disclosed NOV15d polypeptide (SEQ ID NO:42) encoded by SEQ IDNO:41 has 2613 amino acid residues and is presented in Table 15H usingthe one-letter code. NOV15d seems to be a Type II (Ncyt Cexo) membraneprotein with an INTEGRAL Likelihood of −9.39 for Transmembrane 216-232(212-244). Although PSORT suggests that the TEN-M3-like protein may belocalized in the nucleus, the protein of CuraGen Acc. No. CG55069_(—)08predicted here is similar to the TEN-M3 family, some members of whichare membrane localized. Therefore it is likely that this novelTEN-M3-like protein is localized to the same sub-cellular compartment.The SignalP, Psort and/or Hydropathy results predict that NOV15d has nosignal peptide and is likely to be localized in the nucleus with acertainty of 0.8000. In an alternative embodiment, NOV15d is likely tobe localized to the plasma membrane with a certainty of 0.7900, or tothe microbody (peroxisome) with a certainty of 0.3642, or to the Golgibody with a certainty of 0.3000. TABLE 15H NOV15d protein sequenceMDVKERRPYCSLTKSRREKERRYTNSSADNEECRVPTQKSYSSSETLKAFDHDSSRLLYG (SEQ IDNO:42) NRVKDLVHREADEFTRQEQPASNQGQSTLQPLPPSHKQHSAQHHPSITSLNRNSLTNRRNQSPAPPAALPAELQTTPESVQLQDSWVLGSNVPLESRHFLFKTGTGTTPLFSTATPGYTMASGSVYSPPTRPLPRNTLSRSAFKFKKSSKYCSWKCTALCAVGVSVLLAILLSYFIAMHLFGLNWQLQQTENDTFENGKVNSDTMPTNTVSLPSGDNGKLGGFTQENNTIDSGELDIGRRAIQEIPPGIFWRSQLFIDQPQFLKFNISLQKDALIGVYGRKGLPPSHTQYDFVELLDGSRLIAREQRSLLETERAGRQARSVSLHEAGFIQYLDSGIWHLAFYNDGKNAEQVSFNTIVIESVVECPRNCHGNGECVSGTCHCFPGFLGPDCSRAACPVLCSGNGQYSKGRCLCFSGWKGTECDVPTTQCIDPQCGGRGICIMGSCACNSGYKGESCEEADCIDPGCSNHGVCIHGECHCSPGWGGSNCEILKTMCPDQCSGHGTYLQESGSCTCDPNWTGPDCSNEICSVDCGSHGVCMGGTCRCEEGWTGPTCNQRACHPRCAEHGTCKDGKCECSHGWNGEHCTIEGCPGLCNSNGRCTLDQNGWHCVCQPGWRGAGCDVAMETLCTDSKDNEGDGLIDCMDPDCCLQSSCQNQPYCRGLPDPQDIISQSLQSPSQQAAKSFYDRISFLIGSDSTHVIPGESPFNKSLASVIRGQVLTADGTPLIGVNVSFFHYPEYGYTITRQDGMFDLVANGGASLTLVFERSPFLTQYHTVWIPWNVFYVMDTLVMEKEENDIPSCDLSGFVRPNPIIVSSPLSTFFRSSPEDSPIIPETQVLHEETTIPGTDLKLSYLSSRAAGYKSVLKITMTQSIIPFNLMKVHLMVAVVGRLFQKWFPASPNLAYTFIWDKTDAYNQKVYGLSEAVVSVGYEYESCLDLTLWEKRTAILQGYELDASNMGGWTLDKHHVLDVQNGILYKGNGENQFISQQPPVVSSIMGNGRRRSISCPSCNGQADGNKLLAPVALACGIDGSLYVGDFNYVRRIFPSGNVTSVLELRNKDFRHSSNPAHRYYLATDPVTGDLYVSDTNTRRIYRPKSLTGAKDLTKNAEVVAGTGEQCLPFDEARCGDGGKAVEATLMSPKGMAVDKNGLIYFVDGTMIRKVDQNGIISTLLGSNDLTSARPLTCDTSMHISQVRLEWPTDLAINPMDNSIYVLDNNVVLQITENRQVRIAAGRPMHCQVPGVEYPVGKHAVQTTLESATAIAVSYSGVLYITETDEKKINRIRQVTTDGEISLVAGIPSECDCKNDANCDCYQSGDGYAKDAKLSAPSSLAASPDGTLYIADLGNIRIRAVSKNKPLLNSMNFYEVASPTDQELYIFDINGTHQYTVSLVTGDYLYNFSYSNDNDITAVTDSNGNTLRIRRDPNRMPVRVVSPDNQVIWLTIGTNGCLKGMTAQGLELVLFTYHGNSGLLATKSDETGWTTFFDYDSEGRLTNVTFPTGVVTNLHGDMDKAITVDIESSSREEDVSITSNLSSIDSFYTMVQDQLRNSYQIGYDGSLRIIYASGLDSHYQTEPHVLAGTANPTVAKRNMTLPGENGQNLVEWRFRKEQAQGKVNVFGRKLRVNGRNLLSVDFDRTTKTEKIYDDHRKFLLRIAYDTSGHPTLWLPSSKLMAVNVTYSSTGQIASIQRGTTSEKVDYDGQGRIVSRVFADGKTWSYTYLEKSMVLLLHSQRQYIFEYDMWDRLSAITMPSVARHTMQTIRSIGYYRNIYNPPESNASIITDYNEEGLLLQTAFLGTSRRVLFKYRRQTRLSEILYDSTRVSFTYDETAGVLKTVNLQSDGFICTIRYRQIGPLIDRQIFRFSEDGMVNARFDYSYDNSFRVTSMQGVINETPLPIDLYQFDDISGKVEQFGKFGVIYYDINQIISTAVMTYTKHFDAHGRIKEIQYEIFRSLMYWITIQYDNMGRVTKREIKIGPFANTTKYAYEYDVDGQLQTVYLNEKIMWRYNYDLNGNLHLLNPSNSARLTPLRYDLRDRITRLGDVQYRLDEDGFLRQRGTEIFEYSSKGLLTRVYSKGSGWTVIYRYDGLGRRVSSKTSLGQHLQFFYADLTYPTRITHVYNHSSSEITSLYYDLQGHLFAMEISSGDEFYIASDNTGTPLAVFSSNGLMLKQIQYTAYGEIYFDSNIDFQLVIGFHGGLYDPLTKLIHFGERDYDILAGRWTTPDIEIWKRIGKDPAPFNLYMFRNNNPASKIHDVKDYITDVNSWLVTFGFHLHNAIPGFPVPKFDLTEPSYELVKSQQWDDIPPIFGVQQQVARQAKAFLSLGKMAEVQVSRRRAGGAQSWLWFATVKSLIGKGVMLAVSQGRVQTNVLNIANEDCIKVAAVLNNAFYLENLHFTIEGKDTHYFIKTTTPESDLGTLRLTSGRKALENGINVTVSQSTTVVNGRTRRFADVEMQFGALALHVRYGMTLDEEKARILEQARQRALARAWAREQQRVRDGEEGARLWTEGEKRQLLSAGKVQGYDGYYVLSVEQYPELADSANNIQFLRQSEIGRR

[0307] The full amino acid sequence of the protein of the invention wasfound to have 2496 of 2568 amino acid residues (97%) identical to, and2527 of 2568 amino acid residues (98%) similar to, the 2715 amino acidresidue ptnr:SPTREMBL-ACC:Q9WTS6 protein from Mus musculus (Mouse)(TEN-M3).

[0308] The TEN-M3-like gene disclosed in this invention is expressed inat least the following tissues: Adipose, Heart, Aorta, Coronary Artery,Parathyroid Gland, Pineal Gland, Colon, Spleen, Lymph node, Bone,Cartilage, Muscle, Smooth Muscle, Brain, Cerebellum, Right Cerebellum,Pituitary Gland, Temporal Lobe, Hippocampus, Cervix, Mammarygland/Breast, Ovary, Placenta, Uterus, Vulva, Prostate, Testis, Lung,Kidney, Retina, Skin, Dermis.

[0309] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: Cardiomyopathy,Atherosclerosis, Hypertension, Congenital heart defects, Aorticstenosis, Atrial septal defect (ASD), Atrioventricular (A-V) canaldefect, Ductus arteriosus, Pulmonary stenosis, Subaortic stenosis,Ventricular septal defect (VSD), valve diseases, Tuberous sclerosis,Scleroderma, Obesity, Transplantation, Metabolic Disorders, Diabetes,Aneurysm, Fibromuscular dysplasia, Stroke, Myocardial infarction,Embolism, Cardiovascular disorders, Bypass surgery, Hyperparathyroidism,Hypoparathyroidism, Hyperthyroidism, Hypothyroidism, cancer, includingbut not limited to colon, lung, brain, leukemia, breast, ovarian,uterine, prostate, testicular, kidney and skin; SIDS, Lymphedema,Allergies, Osteoporosis, Hypercalceimia, Arthritis, Ankylosingspondylitis, Scoliosis; Tendinitis; Muscular dystrophy, Lesch-Nyhansyndrome, Myasthenia gravis; Von Hippel-Lindau (VHL) syndrome,Alzheimer's disease, Stroke, Tuberous sclerosis, hypercalceimia,Parkinson's disease, Huntington's disease, Cerebral palsy, Epilepsy,Lesch-Nyhan syndrome, Multiple sclerosis, Ataxia-telangiectasia,Leukodystrophies, Behavioral disorders, Addiction, Anxiety, Pain,Neuroprotection; Endocrine dysfunctions, Growth and reproductivedisorders; Fertility; Endometriosis, Autoimmune disease, Asthma,Emphysema, Scleroderma, ARDS, Psoriasis, Actinic keratosis, Tuberoussclerosis, Acne, Hair growth, allopecia, pigmentation disorders, Renalartery stenosis, Interstitial nephritis, Glomerulonephritis, Polycystickidney disease, Systemic lupus erythematosus, Renal tubular acidosis,IgA nephropathy, Hypercalceimia, Lesch-Nyhan syndrome, CNS disorders,neuronal developmental disorders, heart diseases such as stroke,mycocardial infarction, ischemia, localized and systemic scleroderma,pleural inflammatory and fibrotic diseases as well as other diseases,disorders and conditions.

[0310] NOV15a, NOV15b, NOV15c, and NOV15d share a high degree ofhomology as is shown in the amino acid alignment in Table 15I.

[0311] In a search of public sequence databases, NOV15a was found tohave homology to the amino acid sequences shown in the BLASTP datalisted in Table 15J. TABLE 15J BLASTP results for NOV15a Gene Index/Length Identity Positives Identifier Protein/Organism (aa) (%) (%)Expect ptnr:SPTREMBL- TEN-M3 - Mus musculus 2715 2663/2725 2696/2725 0.0ACO:Q9WTS6 (97%) (98%) ptnr:SPTREMBL- TEN-M3 - Brachydanio 25902004/2579 2255/2579 0.0 ACC:Q9W7R4 rerio (Zebrafish) (77%) (87%) (Zebradanio) ptnr:SPTREMBL- ODZ3 - Mus musculus 2346 2015/2182 2053/2182 0.0ACC:Q9JLC1 (92%) (94%) ptnr:SPTREMBL- TEN-M4 - Mus musculus 27711752/2637 2098/2637 0.0 ACC:Q9WTS7 (66%) (79%) ptnr:SPTREMBL- KIAA14S5PROTEIN - 1769 1767/1769 1768/1769 0.0 ACC:Q9P273 Homo sapiens (99%)(99%)

[0312] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 15K. TABLE 15K Patp BLASTP Analysis for NOV15a Sequences producingHigh-scoring Length Identity Positive Segment Pairs Protein/Organism(aa) (%) (%) E Value patp:AAM78695 Human protein SEQ ID NO 21361255/2137 1625/2137 0.0 1357 - Homo sapiens (58%) (76%) patp:AAB92858Human protein sequence 1045 1045/1045 1045/1045 0.0 SEQ ID NO:11431 -Homo (100%) (100%) sapiens patp:AA393294 Human protein sequence 964964/964 964/964 0.0 SEQ ID NO:12355 - Homo (100%) (100%) sapienspatp:AAB92780 Human protein sequence 625 625/625 625/625 0.0 SEQ IDNO:11266 - Homo (100%) (100%) sapiens patp:AAM79679 Human protein SEQ IDNO 1015 569/1009 741/1009 2.6e-308 3325 - Homo sapiens (56%) (73%)

[0313] Table 15L lists the domain description from DOMAIN analysisresults against NOV15a. TABLE 15L Domain Analysis of NOV15a Pfamanalysis Model Domain seq-f seq-t hmm-f hmm-t score E-va1ue EGF 1/7 /522 548 ..   1  45 [ ] 12.8   1.6 EGF 2/7  586  613 ..   1  45 [ ] 16.5 0.63 EGF 3/7  618  645 ..   1  45 [ ] 19.3 0.093 TIL 1/1  604  652 ..  1  67 [ ] −15.5   9.9 EGF 4/7  652  680 ..   1  45 [ ] 13.3   1.4 EGF5/7  685  711 ..   1  45 [ ] 12.2   1.8 EGF 6/7  716  742 ..   1  45 [ ]21.3 0.023 EGF 7/7  762  792 ..   1  45 [ ] 14.5   1.1 ATHILA 1/1 12171234 .. 355 372 ..  3.2   2.1 NHL 1/2 1368 1395 ..   1  30 []  9.8   1.7NHL 2/2 1497 1524 ..   1  30 [] 10.5   1.3 Glyco_hydro_38 1/1 1845 1870.. 688 715 .]  4.3   1.3 Alignments of top-scoring domains: EGF: domain1 of 7, from 522 to 548: score 12.8, E = 1.6 (SEQ ID NO:182)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<- 51+   +|+++|+||++           ||+| ||     + |++| NOV15a 522CPR--NCHGNGECVSG-----------TCHCFPG-----FLGPDC 548 EGF: domain 2 of 7,from 586 to 613: score 16.5, E = 0.63 (SEQ ID NO:183)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-↑ ++  | ++|+|+ +           +| |  |     | |+ | NOV15a 586CIDP-QCGGRGICIMG-----------SCACSSG-----YKGESC 613 EGF: domain 3 of 7,from 618 to 645: score 19.3, E = 0.093 (SEQ ID NO:184)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-| ++ +|||+|+|+ +           +|+| ||     + | +| NOV15a 618CIDP-GCSNHGVCIHG-----------ECHCSPG-----WGGSNC 645 TIL: domain 1 of 1,from 604 to 652: score -15.5, E = 9.9 (SEQ ID NO:185)CpaneqyteCgpsCepsCsnpdgplettppCegtSpkvPstCkeg.C|       +|    |+ | +|         |       + +|+ |+| NOV15a 604CSSGYKGESCE---EADCIDPG--------CS-----NHGVCIHGeC 634vCqpGyVrnndgdkCVprseC<-*  |+||   +| +   ++++ | 635 HCSPGWGGSNCE---ILKTMC652 EGF: domain 4 of 7, from 652 to 680: score 13.3, E = 1.4 (SEQ IDNO:186) CapnnpCsngGtCvntpggssdNfggytCeCppGdyylsytGkrC<-|++   ||++|| +   |         +|+| |      +||++| NOV15a 652CPD--QCSGHGTYLQESG---------SCTCDPN-----WTGPDC 680 EGF: domain 5 of 7,from 685 to 711: score 12.2, E = 1.8 (SEQ ID NO:187)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+    |  +|+|+ +           ||+| +|     +||+ | NOV15a 685CSV--DCGSHGVCMGG-----------TCRCEEG-----WTGPAC 711 EGF: domain 6 of 7,from 716 to 742: score 21.3, E = 0.023 (SEQ ID NO:188)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+|   | ++||| ++           +||| +|     ++|++| NOV15a 716CHP--RCAEHGTCKDG-----------KCECSQG-----WNGEHC 742 EGF: domain 7 of 7,from 762 to 792: score 14.5, E = 1.1 (SEQ ID NO:189)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+    |+ +|+|+   +       | +|+|+||     + |  | NOV15a 762CPG--LCNSNGRCTLDQN-------GGHCVCQPG-----WRGAGC 792 ATHILA: domain 1 of 1,from 1217 to 1234: score 3.2, E = 2.1 (SEQ ID NO:190)LPceevTsIierdNIdFk<-* +|+ +|||++| +|+||+ NOV15a 1217 FPSGNVTSVLELRNKDFR1234 NHL: domain 1 of 2, from 1368 to 1395: score 9.8, e = 1.7 (SEQ IDNO:191) fdrPrGvavdpsdGqivVaDqsenhriqvF<-* + +|+++|++| |+ |+| |  +|  +|+NOV15a 1368 LEWPTDLAINPMDNSIYVLD--NNVVLQIT 1395 NHL: domain 2 of 2, from1497 to 1524: score 10.5, E = 1.3 (SEQ ID NO:192)fdrPrGvavdpsdGqivVaDqsenhriqvF<-* +  | ++|+  +|| +++||  +| || NOV15a1497 LSAPSSLAAS-PDGTLYIAD-LGNIRIRAV 1524 Glyco_hydrO_38: domain 1 of 1,from 1845 to 1870: score 4.3, E = 1.3 (SEQ ID NO:193)lkveFdeletGllksitrkqdnktvhvn<-* ++| ++   || ++||+| ++  +|+++ NOV15a 1845VNVTYS--STGQIASIQRGTTSEKVDYD 1870

[0314] In a search of public sequence databases, NOV15d was found tohave homology to the amino acid sequences shown in the BLASTP datalisted in Table 15M. TABLE 15M BLASTP results for NOV15d Gene Index/Length Identity Positives Identifier Protein/Organism (aa) (%) (%)Expect ptnr:SPTREMBL- TEN-M3 - Mus musculus 2715 2496/2568 2527/2568 0.0ACC:Q9WTS6 (97%) (98%) ptnr:SPTREMBL- ODZ3 - Mus musculus 2346 2309/23532334/2353 0.0 ACC:Q9JLC1 (98%) (99%) ptnr:SPTREMBL- TEN-M3 - Brachydanio2590 2117/2576 2352/2576 0.0 ACC:Q9W7R4 rerio (Zebrafish) (82%) (91%)(Zebra danio) ptnr:SPTREMBL- NEURESTIN ALPHA - 2765 1783/2534 2135/25340.0 ACC:Q9R1K2 Rattus norvegicus (70%) (84%) ptnr:SPTREMBL- TENEURIN-2 -Gallus 2802 1779/2536 2143/2536 0.0 ACC:Q9DER5 gallus (70%) (84%)

[0315] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 15N. TABLE 15N Patp BLASTP Analysis for NOV15 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAM78695 Human protein SEQ ID 2136 1185/19621521/1962 0.0 NO 1357 - Homo sapiens (60%) (77%) patp:AAB92858 Humanprotein sequence 1045 1045/1045 1045/1045 0.0 SEQ ID NO:11431 - Homo(100%) (100%) sapiens patp:AA393294 Human protein sequence 964 964/964964/964 0.0 SEQ ID NO:12355 - Homo (100%) (100%) sapiens patp:AAB92780Human protein sequence 625 625/625 625/625 0.0 SEQ ID NO:11266 - Homo(100%) (100%) sapiens patp:AAM79679 Human protein SEQ ID 1015 569/1009741/1009 2.6e-308 NO 3325 - Homo sapiens (56%) (73%)

[0316] Table 15O lists the domain description from DOMAIN analysisresults against NOV15d. TABLE 15O Domain Analysis of NOV15d Pfamanalysis Model Domain seq-f seq-t hmm-f hmm-t score E-value EGF 1/7  425451 .. 1 45 [ ] 12.8 1.6 EGF 2/7 489  516 .. 1 45 [ ] 14.8 1 EGF 3/7 521 548 .. 1 45 [ ] 19.3 0.093 EGF 4/7 555  583 .. 1 45 [ ] 13.3 1.4 EGF5/7 588  614 .. 1 45 [ ] 14.1 1.2 EGF 6/7 619  645 .. 1 45 [ ] 21.00.027 EGF 7/7 650  680 .. 1 45 [ ] 17.2 0.38 ATHILA 1/1 1105 1122 .. 355372 . . 3.2 2.1 NHL 1/2 1256 1283 .. 1 30 [ ] 9.8 1.7 NHL 2/2 1385 1412.. 1 30 [ ] 10.5 1.3 Glyco_hydro_38 1/1 1733 1758 .. 688 715 .] 4.3 1.3Alignments of top-scoring domains: EGF: domain 1 of 7, from 425 to 451:score 12.8, E = 1.6 (SEQ ID NO:196)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+   +|+++|+||++           ||+| ||     + |++| NOV15d 425CPR--NCHGNGECVSG-----------TCHCFPG-----FLGPDC 451 EGF: domain 2 of 7,from 489 to 516: score 14.8, E = 1 (SEQ ID NO:197)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-| ++  | ++|+|+ +           +| |  |     | |+ | NOV15d 489CIDP-QCGGRGICIMG-----------SCACNSG-----YKGESC 516 EGF: domain 3 of 7,from 521 to 548: score 19.3, E = 0.093 (SEQ ID NO:198)CapnnpCsngGtCvntpggssdNfggytCeCppGdyylsytGkrC<-| ++ +|||+|+|+ +           +|+| ||     + | +| NOV15d 521CIDP-GCSNHGVCIHG-----------ECHCSPG-----WGGSNC 548 EGF: domain 4 of 7,from 555 to 583: score 13.3, E = 1.4 (SEQ ID NO:199)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|++   ||++|| +   |         +|+| |      +||++| NOV15d 555CPD--QCSGHGTYLQESG---------SCTCDPN-----WTGPDC 583 EGF: domain 5 of 7,from 588 to 614: score 14.1, E = 1.2 (SEQ ID NO:200)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+    |  +|+|+ +           ||+| +|     +||++| NOV15d 588CSV--DCGSHGVCMGG-----------TCRCEEG-----WTGPTC 614 EGF: domain 6 of 7,from 619 to 645: score 21.0, E = 0.027 (SEQ ID NO:201)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+|   | ++||| ++           +||| +|     ++|++| NOV15d 619CHP--RCAEHGTCKDG-----------KCECSHG-----WNGEHC 645 EGF: domain 7 of 7,from 650 to 680: score 17.2, E = 0.38 (SEQ ID NO:202)CapnnpCsngGtCvntpggssdnfggytCeCppGdyylsytGkrC<-|+    |+ +|+|+   +       | +|+|+||     + |  | NOV15d 650CPG--LCNSNGRCTLDQN-------GWHCVCQPG-----WRGAGC 680 ATHILA: domain 1 of 1,from 1105 to 1122: score 3.2, E = 2.1 (SEQ ID NO:203)LPceevTsTierdnIdFk<-* +|+ +|||++| +|+||+ NOV15d 1105 FPSGNVTSVLELRNKDFR1122 NHL: domain 1 of 2, from 1256 to 1283: score 9.8, E = 1.7 (SEQ IDNO:204) fdrPrGvavdpsdGqivVaDqsenhriqvF<-* + +|+++|++| |+ |+| |  +|  +|+NOV15d 1256 LEWPTDLAINPMDNSIYVLD--NNVVLQIT 1283 NHL: domain 2 of 2, from1385 to 1412: score 10.5, E = 1.3 (SEQ ID NO:205)fdrPrGvavdpsdGqivVaDqsenhriqvF<-* +  | ++|+  +|| +++||  +| || NOV15d1385 LSAPSSLAAS-PDGTLYIAD-LGNIRIRAV 1412 Glyco_hydro_38: domain 1 of 1,from 1733 to 1758: score 4.3, E = 1.3 (SEQ ID NO:206)lkveFdeletGllksitrkqdnktvhvn<-* ++| ++   || ++||+| ++  +|+++ NOV15d 1733VNVTYS--STGQIASIQRGTTSEKVDYD 1758

[0317] EGF-like domain (IPR000561): A sequence of about thirty to fortyamino-acid residues long found in the sequence of epidermal growthfactor (EGF) has been shown to be present, in a more or less conservedform, in a large number of other, mostly animal proteins. The list ofproteins currently known to contain one or more copies of an EGF-likepattern is large and varied. The functional significance of EGF domainsin what appear to be unrelated proteins is not yet clear. However, acommon feature is that these repeats are found in the extracellulardomain of membrane-bound proteins or in proteins known to be secreted(exception: prostaglandin G/H synthase). The EGF domain includes sixcysteine residues which have been shown (in EGF) to be involved indisulfide bonds. The main structure is a two-stranded beta-sheetfollowed by a loop to a C-terminal short two-stranded sheet. Subdomainsbetween the conserved cysteines vary in length. (Campbell I. D., BorkP., 1993, Curr. Opin. Struct. Biol. 3: 385-392; Weber I. T., Appella E.,Blasi F., 1988, FEBS Lett. 231: 1-4; Doolittle R. F., Feng D. F.,Johnson M. S., 1984, Nature 307: 558-560; Davis C. G., 1990, New Biol.2: 410-419; Hunt L. T., Barker W. C., Blomquist M. C., 1984, Proc. Natl.Acad. Sci. U.S.A. 81: 7363-7367; Hunt L. T., Barker W. C., George D. G.,Johnson G. C., 1986, Protein Nucleic Acid Enz. 29: 54-68).

[0318] This indicates that the sequence of the invention has propertiessimilar to those of other proteins known to contain this/these domain(s)and similar to the properties of these domains.

[0319] The establishment of periodic patterns during the development ofthe Drosophila embryo is controlled by genes that act in a hierarchicalmanner (Nuisslein-Volhard and Wieschhaus, 1980, Nature 287: 795-801;Ingham 1988, Nature 335: 25-34; St. Johnston and Nuisslein-Volhard,1992, Cell 68: 201-219). Maternal activities induce the expression oftranscription factors, encoded by gap genes, which regulate theexpression of other transcription factors encoded by pair rule genes.Pair rule genes are expressed in seven stripes along theanterior-posterior axis of Drosophila melanogaster. Their expression iscrucial for the consecutive expression of segment polarity genes and theestablishment of the segmental pattern of Drosophila embryos. Mutationsin pair rule genes result in deletions of cuticle segments which appearin a reiterative manner along the body axis of the hatched larvae. Allknown pair rule genes code for transcription factors, except for a geneidentified independently in two laboratories and designated ten-m(Baumgartner et al., 1994, EMBO J. 13: 3728-3740) and odz (Levine etal., 1994, EMBO J. 13: 3728-3740). ten-m and odz are identical genes andmutations lead to a pair rule phenotype similar to odd-paired in whichevery other segment is missing (Nisslein-Volhard et al., 1995, ColdSpring Harb. Symp. Quant. Biol. 50: 145-154). Despite the fact that bothreports showed identical sequences, Ten-m was described as a secretedDrosophila tenascin-like molecule and Odz as a type I transmembranereceptor. Tenascins are a family of extracellular matrix proteins with amodular structure composed of fibronectin type III (FNIII) repeats,EGF-like repeats, and a COOH-terminal fibrinogen-like repeat (Erickson,1993, Curr. Opin. Cell Biol. 5: 869-876). Biochemical studies using aDrosophila cell line indicated that Ten-m is a large secretedproteoglycan with chondroitinase ABC-sensitive chondroitin sulfateand/or dermatan sulfate side chains. The core protein was reported tocontain EGF-like and FNIII repeats, but to lack the fibrinogen-likedomain (Baumgartner et al., 1994, EMBO J. 13: 3728-3740). Odz wasisolated as a novel phosphotyrosine-containing protein (Levine et al.,1994, Cell 77: 587-598). A transmembrane region was predictedCOOH-terminal of the EGF repeats, followed by the cytoplasmic domaincontaining several tyrosine kinase phosphorylation consensus sites. Morerecently, Wang et al. (1998, EMBO J. 17: 3619-3630) described amammalian orthologue of Ten-m/Odz, termed DOC4 (downstream of chop),which is induced by the stress-induced transcription factor CHOP. Theopen reading frame of DOC4 shares 31% sequence identity and 50% sequencesimilarity with Ten-m/Odz. Furthermore, DOC4 contains a short stretch ofhydrophobic amino acids ˜400 amino acids COOH-terminal of the putativestart codon. This together with the cell surface localization led to thesuggestion that DOC4 may constitute a type II transmembrane molecule.Ten-m/Odz, as well as DOC4, contains a stretch of eight consecutiveEGF-like modules which are most similar to the EGF repeats of tenascins.EGF modules are structural units of proteins or parts of protein,located extracellularly. They can occur as isolated modules such as inreelin (D'Arcangelo et al., 1995, Nature. 374: 719-723) and in selectins(Whelan, 1996, Trends Biochem. Sci. 21: 65-69), or in arrays like innotch (Fleming et al., 1997, Development. 124: 2973-2981) and tenascins(Spring et al., 1989, Cell. 59: 325-334). A conserved feature of the EGFdomain in Ten-m/Odz, DOC4, and Ten-a, a Drosophila molecule related toTen-m/Odz (Baumgartner and Chiquet-Ehrismann, 1993, Mech. Dev. 40:165-176), is the substitution of a cysteine residue with an aromaticamino acid in two of the eight EGF-like modules. This leaves twocysteines with no intramodular partner. The importance of the integrityof the cysteine patterns in EGF-like modules is exemplified by thefunctional impairment of notch 3, which has been observed in patientswith an autosomal dominant disorder causing stroke (Joutel et al., 1997,Lancet. 350: 1511-1515). The molecular basis of this disease ispredominantly the substitution of cysteines with other amino acids inthe EGF modules of notch 3. The observation that the EGF-like modules ofTen-m/Odz with five cysteines are ontogenetically conserved indicatesthat they are able to fold into a structure which might be important forthe function of the protein.

[0320] Many genes that control pattern formation are expressed atseveral different periods during development to function in a variety ofprocesses both during embryogenesis and postnatal life. After theinitial expression in seven stripes at the cellular blastoderm stage,ten-m/odz is downregulated and appears at later stages in the centralnervous system (CNS), dorsal vessel, trachea, and the eye and discsgiving rise to the cephalic (antenna), ventral (wing), and dorsal (legs)thoracic appendages (Baumgartner et al., 1994, EMBO J. 13: 3728-3740;Levine et al., 1994, EMBO J. 13: 3728-3740). The highest level ofTen-m/Odz expression is observed in the CNS where the protein isdeposited on the surface of axons (Levine et al., 1997, Dev. Dyn. 209:1-14). The Drosophila eye disk is another location where high levels ofTen-m/Odz are found in very distinct sites including the morphogeneticfurrow, photoreceptor-like cells, and nonepithelial cells of the eyedisc (Levine et al., 1997, Dev. Dyn. 209: 1-14). The expression patternof DOC4 in mammals is not well characterized but the presence of themRNA has been demonstrated in the developing mouse brain (Wang et al.,1998, EMBO J. 17: 3619-3630).

[0321] Several mutations in the ten-m/odz gene have been identified, allresulting in embryonic lethality (Baumgartner et al., 1994, EMBO J. 13:3728-3740; Levine et al., 1994, EMBO J. 13: 3728-3740). Due to the lackof viable hypomorphic mutations, it is not clear whether the proteinexecutes an important function in all sites where it is expressed. Onepossible function for Ten-m/Odz comes from studies with DOC4 which hasbeen isolated in search of GADD153/CHOP (growth arrest and DNAdamage/C/EBP homology protein)-induced mRNA. GADD153/CHOP is responsiveto many forms of stress, including alkylating agents, UV light, andconditions that trigger an ER stress response. For example, ER stresswhich occurs during ischemia alters proliferation of cells, induces celldeath, and the expression of GADD153/CHOP (Zinszner et al., 1998, GenesDev. 12: 982-995). Recent studies have shown that GADD153/CHOP exerts atleast part of its function via the induction of DOC4 and other proteins(Wang et al., 1998, EMBO J. 17: 3619-3630).

[0322] Recently, Oohashi et al. (1999, J. Cell Biol. 145: 563-577) haveshown that at least four different cDNAs with similarity to theDrosophila ten-m/odz cDNA are expressed in mice. One of them, ten-m4, isidentical to the DOC4 cDNA. The alignment of the four deduced mouseprotein sequences indicated a strong conservation of the characteristicfeatures for type II transmembrane molecules, which was also recognizedfor DOC4. In addition, the recombinant production of the putativeextracellular domain of Ten-m1 revealed the formation of dimericstructures. The dimerization of Ten-ml is mediated via the singlecysteine residues in the EGF modules that lack their intramodularpartners. Also, Ten-m1 is able to make homophilic interactions.

[0323] CD79 alpha is a subunit of an intracytoplasmic protein reportedto be specific for B lymphocytes, including immature B lineage cells. Toevaluate expression of the CD79 alpha antigen in acute myeloid leukemia(AML), we studied forty-eight cases of AML by paraffin sectionimmunohistochemistry. The cases included four MO, nine M1, nine M2, tenM3, ten M4, and six M5 AMLs using criteria of theFrench-American-British cooperative group. Eleven cases demonstratedcytoplasmic staining for the CD79 alpha antigen, including one M1, nineM3, and one M5 AML. These CD79 alpha-positive cases represented 5% ofall non-promyelocytic AMLs and 90% of all acute promyelocytic leukemiasstudied. All acute promyelocytic leukemias had the characteristic t(i5;17)(q24;q21), including two cases of the microgranular variant (M3v).No other B-lineage-associated antigens were found in the CD79alpha-positive cases, with the exception of a subpopulation ofCD19-positive leukemic cells in one patient. The two non-promyelocyticleukemias that expressed CD79 alpha had no evidence of t(15;17) and didnot express any additional B-lineage-associated antigens that mightsuggest a mixed lineage proliferation. This study demonstrates that CD79alpha expression in acute leukemia is not restricted to B-lineage acutelymphoblastic leukemias and that CD79 alpha expression is frequentlyassociated with t(15; 17) acute myeloid leukemia.

[0324] NOV16

[0325] NOV16 includes five novel Aldose Reductase-like proteinsdisclosed below. The disclosed sequences have been named NOV16a, NOV16b,NOV16c, NOV16d, and NOV16e. Unless specifically addressed as NOV16a,NOV16b, NOV16c, NOV16d, or NOV16e, any reference to NOV16 is assumed toencompass all variants.

[0326] NOV16a

[0327] A disclosed NOV16a nucleic acid of 956 nucleotides (also referredto as CG55778-01)(SEQ ID NO:43) encoding a novel Aldose Reductase-likeprotein is shown in Table 16A. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 31-33 and endingwith a TGA codon at nucleotides 937-939. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined. The start and stop codons are in bold in Table16A. TABLE 16A NOV16a nucleotide sequence GGCGGGGCGGCGGGGCGGCCGGCGGCGGCCATGGGAGATATCCCAGCCGTGGGCCTCAGC (SEQ ID NO:43)TCCTGGAAGCAGGCTTCTCCAGGGAAAGTGACCGAGGCAGTGAAAGAGGCCATTGACGCAGGGTACCGGCACTTCGACTGTGCTTACTTTTACCACAATGAGAGGGAGGTTGGAGCAGGGATCCGTTGCAAGATCAAGGAAGGCGCTGTAAGACGGGAGGATCTGTTCATTGCCACTAAGCTGTGGTGCACCTGCCATAAGAAGTCCTTGGTGGAAACAGCATGCAGAAAGAGTCTCAAGGCCTTGAAGCTGAACTATTTGGACCTCTACCTCATACACTGGCCCATGGGTTTCAAGCCTCGAGTGCAGGACTTGCCTCTGGACGAGAGCAACATGGTTATTCCCAGTGACACGGACTTCCTGGACACGTGGGAGGCCATGGAGGACCTGGTGATCACCGGGCTGGTGAAGAACATCGGGGTGTCAAACTTCAACCATGAACAGCTTGAGAGGCTTTTGAATAAGCCTGGGTTGAGGTTCAAGCCACTAACCAACCAGATTGAGTGCCACCCATATCTTACTCAGAAGAATCTGATCAGTTTTTGCCAATCCAGAGATGTGTCCGTGACTGCTTACCGTCCTCTTGGTGGCTCTAGTGAGGGGGTTGACCTGATAGACAACCCTGTGATCAAGAGGATTGCAAAGGAGCACGGCAAGTCTCCTGCTCAGATTTTGATCCGATTTCAAATCCAGAGGAATGTGATAGTGATCCCCGGATCTATCACCCCAAGTCACATTAAAGAGAATATCCAGGTGTTTGATTTTGAATTAACACAGCACGATATGGATAACATCCTCAGCCTAAACAGGAATCTCCGACTGGCCATGTTCCCCAGAACTAAAAATCACAAAGACTATCCTTTCCACATAGAATACTGA GGACGCTTCCCCTTCCT

[0328] The aldose reductase NOV16a disclosed in this invention maps tochromosome 10.

[0329] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 740 of 922 bases(80%) identical to a gb:GENBANK-ID:MMU68535|acc:U68535.1 mRNA from Musmusculus (Mus musculus aldo-keto reductase mRNA, complete cds)

[0330] A disclosed NOV16a polypeptide (SEQ ID NO:44) encoded by SEQ IDNO:43 has 302 amino acid residues and is presented in Table 16B usingthe one-letter code. The SignalP, Psort and/or Hydropathy resultspredict that NOV16a has no signal peptide and is likely to be localizedin the cytoplasm with a certainty of 0.6500. In an alternativeembodiment, NOV16a is likely to be localized to the mitochondrial matrixspace with a certainty of 0.1000 or to the lysosome (lumen) with acertainty of 0.1000. TABLE 16B NOV16a protein sequenceMGDIPAVGLSSWKQASPGKVTEAVKEAIDAGYRHFDCAYFYHNEREVGAGIRCKIKEGAV (SEQ IDNO:44) RREDLFIATKLWCTCHKKSLVETACRKSLKALKLNYLDLYLIHWPMGFKPRVQDLPLDESNMVIPSDTDFLDTWEAMEDLVITGLVKNIGVSNFNHEQLERLLNKPGLRFKPLTNQIECHPYLTQKNLISFCQSRDVSVTAYRPLGGSSEGVDLIDNPVIKRIAKEHGKSPAQILIRFQIQRNVIVIPGSITPSHIKENIQVFDFELTQHDMDNILSLNRNLRLAMFPRTKNHKDYPFHI EY

[0331] The full amino acid sequence of the protein of the invention wasfound to have 223 of 302 amino acid residues (73%) identical to, and 259of 302 amino acid residues (85%) similar to, the 301 amino acid residueptnr:SPTREMBL-ACC:009125 protein from Mus musculus (Mouse) (ALDO-KETOREDUCTASE).

[0332] The aldose reductase disclosed in this invention is expressed inat least the following tissues: lung, testis, germ cell. The nucleicacids and proteins of the invention are useful in potential diagnosticand therapeutic applications implicated in various diseases anddisorders described below and/or other pathologies. For example, thecompositions of the present invention will have efficacy for treatmentof patients suffering from: cancer, trauma, regeneration (in vitro andin vivo), viral/bacterial/parasitic infections, systemic lupuserythematosus, autoimmune disease, asthma, emphysema, scleroderma,allergy, ARDS, infertility and other diseases, disorders and conditionsof the like.

[0333] NOV16b

[0334] A disclosed NOV16b nucleic acid of 875 nucleotides (also referredto as CG55778-02)(SEQ ID NO:45) encoding a novel Aldose Reductase-likeprotein is shown in Table 16C. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 23-25 and endingwith a TGA codon at nucleotides 776-778. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined. The start and stop codons are in bold in Table16C. TABLE 16C NOV16b nucleotide sequence GGCGGGGCGGCCGGCGGCGGCCATGGGAGATATCCCAGCCGTGGGCCTCAGCTCCTGGAA (SEQ ID NO:45)GCAGGCTTCTCCAGGAAAAGTGACCGAGGCAGTGAAAGAGGCCATTGACGCAGGGTACCGGCACTTCGACTGTGCTTACTTTTACCACAATGAGAGGGAGGTTGGAGCAGGGATCCGTTGCAAGATCAAGGAAGGCGCTGTAAGACGGGAGGATCTGTTCATTGCCACTAAGCTGTGGTGCACCTGCCATAAGAAGTCCTTGGTGGAAACAGCATGCAGAAAGGGTCTCAAGGCCTTGAAGCTGAACTATTTGGACCTCTACCTCATACACTGGCCCATGGGTTTCAAGCCTCCTCATCCAGAATGGATCATGAGCTGCAGTGAACTTTCCTTCTGCCTCTCACATCCTCGAGTGCAGGACTTGCCTCTGGACGAGAGCAACATGGTTATTCCCAGTGACACGGACTTCCTGGACACGTGGGAGGCCATGGAGGACCTGGTGATCACCGGGCTGGTGAAGAACATCGGGGTGTCAAACTTCAACCATGAACAGCTTGAGAGGCTTTTGAATAAGCCTGGGTTGAGGTTCAAGCCACTAACCAACCAGATTTTGATCCGATTTCAAATCCAGAGGAATGTGATAGTGATCCCCGGATCTATCACCCCAAGTCACATTAAAGAGAATATCCAGGTGTTTGATTTTGAATTAACACAGCACGATATGGATAACATCCTCAGCCTAAACAGGAATCTCCGACTGGCCATGTTCCCCATGTAA ATATGGCTCCTTCTTTTTAAAACAGAGGGAAGAATATACAGATTGAATGATTGGTGTCTGAATAGAACTAAAAATCACAAAGACTATCCTTTCCACA

[0335] NOV16b is a splice form of CG55778_(—)01 with an alternativelyspliced exon 4, deletion of exon 6 and 7, and a different C-terminuswith exon 10 missing. The aldose reductase NOV16b disclosed in thisinvention maps to chromosome 10.

[0336] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 634 of 657 bases(96%) identical to a gb:GENBANK-ID:AF263242|acc:AF263242.1 mRNA fromHomo sapiens (Homo sapiens aldo-keto reductase loopADR mRNA, completecds).

[0337] A disclosed NOV16b polypeptide (SEQ ID NO:46) encoded by SEQ IDNO:45 has 251 amino acid residues and is presented in Table 16D usingthe one-letter code. The SignalP, Psort and/or Hydropathy resultspredict that NOV16b has no signal peptide and is likely to be localizedin the cytoplasm with a certainty of 0.4500. In an alternativeembodiment, NOV16b is likely to be localized to the microbody(peroxisome) with a certainty of 0.1047, or to the mitochondrial matrixspace with a certainty of 0.1000, or to the lysosome (lumen) with acertainty of 0.1000. TABLE 16D NOV16b protein sequenceMGDIPAVGLSSWKQASPGKVTEAVKEAIDAGYRHFDCAYFYHNEREVGAGIRCKIKEGAV (SEQ IDNO:46) RREDLFIATKLWCTCHKKSLVETACRKGLKALKLNYLDLYLIHWPMGFKPPHPEWIMSCSELSFCLSHPRVQDLPLDESNMVIPSDTDFLDTWEAMEDLVITGLVKNIGVSNFNHEQLERLLNKPGLRFKPLTNQILIRFQIQRNVIVIPGSITPSHIKENIQVFDFELTQNDMDNILSL NRNLRLAMFPM

[0338] The full amino acid sequence of the protein of the invention wasfound to have 197 of 207 amino acid residues (95%) identical to, and 200of 207 amino acid residues (96%) similar to, the 320 amino acid residueptnr:TREMBLNEW-ACC:AAK58523 protein from Homo sapiens (Human) (ALDO-KETOREDUCTASE LOOPADR).

[0339] The ALDOSE REDUCTASE-like gene disclosed in this invention isexpressed in at least the following tissues: lung, testis, germ cell.The nucleic acids and proteins of the invention have applications in thediagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: cancer, trauma,regeneration (in vitro and in vivo), viral/bacterial/parasiticinfections, systemic lupus erythematosus, autoimmune disease, asthma,emphysema, scleroderma, allergy, ARDS, infertility, as well as otherdiseases, disorders and conditions.

[0340] NOV16c

[0341] A disclosed NOV16c nucleic acid of 752 nucleotides (also referredto as CG55778-03)(SEQ ID NO:47) encoding a novel Aldose Reductase-likeprotein is shown in Table 16E. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 23-25 and endingwith a TAA codon at nucleotides 653-655. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined. The start and stop codons are in bold in Table16E. TABLE 16E NOV16c nucleotide sequence GGCGGGGCGGCCGGCGGCGGCCATGGGAGATATCCCAGCCGTGGGCCTCAGCTCCTGGAA (SEQ ID NO:47)GCAGGCTTCTCCAGGTAAAGTGACCGAGGCAGTGAAAGAGGCCATTGACGCAGGGTACCGGCACTTCGACTGTGCTTACTTTTACCACAATGAGAGGGAGGTTGGAGCAGGGATCCGTTGCAAGATCAAGGAAGGCGCTGTAAGACGGGAGGATCTGTTCATTGCCACTAAGCTGTGGTGCACCTGCCATAAGAAGTCCTTGGTGGAAACAGCATGCAGAAAGAGTCTCAAGGCCTTGAAGCTGAACTATTTGGACCTCTACCTCATACACTGGCCCATGGGTTTCAAGCCTCCTCATCCAGAATGGATCATGAGCTGCAGTGAACTTTCCTTCTGCCTCTCACATCCTCGAGTGCAGGACTTGCCTCTGGACGAGAGCAACATGGTTATTCCCAGTGACACGGACTTCCTGGACACGTGGGAGATTTTGATCCGATTTCAAATCCAGAGGAATGTGATAGTGATCCCCGGATCTATCACCCCAAGTCACATTAAAGAGAATATCCAGGTGTTTGATTTTGAATTAACACAGCACGATATGGATAACATCCTCAGCCTAAACAAGAATCTCCGACTGGCCATGTTCCCCATGTAA ATATGGCTCCTTCTTTTTAAAACAGAGGGAAGAATATACAGATTGAATGATTGGTGTCTGAATAGAACTAAAAATCACAAAGACTATCCTTTCCACA

[0342] NOV16c is a splice form of Aldo-Keto Reductase with analternatively spliced exon 4, deletion of exons 5, 6, and 7, and adifferent C-terminus with exon 10 missing. The aldose reductase NOV16cdisclosed in this invention maps to chromosome 10.

[0343] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 478 of 482 bases(99%) identical to a gb:GENBANK-ID:AF263242|acc:AF263242.1 mRNA fromHomo sapiens (Homo sapiens aldo-keto reductase loopADR mRNA, completecds).

[0344] A disclosed NOV16c polypeptide (SEQ ID NO:48) encoded by SEQ IDNO:47 has 210 amino acid residues and is presented in Table 16F usingthe one-letter code. The SignalP, Psort and/or Hydropathy resultspredict that NOV16c has no signal peptide and is likely to be localizedin the cytoplasm with a certainty of 0.4500. In an alternativeembodiment, NOV16c is likely to be localized to the microbody(peroxisome) with a certainty of 0.2365, or to the mitochondrial matrixspace with a certainty of 0.1000, or to the lysosome (lumen) with acertainty of 0.1000. TABLE 16F NOV16c protein sequenceMGDIPAVGLSSWKQASPGKVTEAVKEAIDAGYRHFDCAYFYHNEREVGAGIRCKIKEGAV (SEQ IDNO:48) RREDLFIATKLWCTCHKKSLVETACRKSLKALKLNYLDLYLIHWPMGFKPPHPEWIMSCSELSFCLSHPRVQDLPLDESNMVIPSDTDFLDTWEILIRFQIQRNVIVIPGSITPSHIKENIQVFDFELTQHDMDNILSLNKNLRLAMFPM

[0345] The full amino acid sequence of the protein of the invention wasfound to have 153 of 156 amino acid residues (98%) identical to, and 154of 156 amino acid residues (98%) similar to, the 307 amino acid residueptnr:SPTREMBL-ACC:Q9BU71 protein from Homo sapiens (Human) (SIMILAR TOALDO-KETO REDUCTASE).

[0346] The Aldo-Keto Reductase-like gene disclosed in this invention isexpressed in at least the following tissues: lung, testis, germ cell.The sequence is predicted to be expressed in the following tissuesbecause of the expression pattern of (GENBANK-ID:gb:GENBANK-ID:AF263242|acc:AF263242.1) a closely related Homo sapiensaldo-keto reductase loopADR mRNA, complete cds homolog in species Homosapiens: small intestine.

[0347] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: cancer, trauma,regeneration (in vitro and in vivo), viral/bacterial/parasiticinfections, systemic lupus erythematosus, autoimmune disease, asthma,emphysema, scleroderma, allergy, ARDS, infertility, as well as otherdiseases, disorders and conditions.

[0348] NOV16d

[0349] A disclosed NOV16d nucleic acid of 785 nucleotides (also referredto as CG55778-04)(SEQ ID NO:49) encoding a novel Aldose Reductase-likeprotein is shown in Table 16G. An open reading frame was identifiedbeginning with an ATG initiation codon at nucleotides 31-33 and endingwith a TGA codon at nucleotides 766-768. Putative untranslated regionsupstream from the initiation codon and downstream from the terminationcodon are underlined. The start and stop codons are in bold in Table16G. TABLE 16G NOV16d nucleotide sequence GGCGGGGCGGCGGGGCGGCCGGCGGCGGCCATGGGAGATATCCCAGCCGTGGGCCTCAGC (SEQ ID NO:49)TCCTGGAAGCAGGCTTCTCCAGGGAAAGTGACCGAGGCAGTGAAAGAGGCCATTGACGCAGGGTACCGGCACTTCGACTGTGCTTACTTTTACCACAATGAGAGGGAGGTTGGAGCAGGGATCCGTTGCAAGATCAAGGAAGGCGCTGTAAGACGGGAGGATCTGTTCATTGCCACTAAGCTGTGGTGCACCTGCCATAAGAAGTCCTTGGTGGAAACAGCATGCAGAAAGAGTCTCAAGGCCTTGAAGCTGAACTATTTGGACCTCTACCTCATACACTGGCCCATGGGTTTCAAGCCTCGAGTGCAGGACTTGCCTCTGGACGAGAGCAACATGGTTATTCCCAGTGACACGGACTTCCTGGACACGTGGGAGGCCATGGAGGACCTGGTGATCACCGGGCTGGTGAAGAACATCGGGGTGTCAAACTTCAACCATGAACAGCTTGAGAGGCTTTTGAATAAGCCTGGGTTGAGGTTCAAGCCACTAACCAACCAGATTTTGATCCGATTTCAAATCCAGAGGAATGTGATAGTGATCCCCGGATCTATCACCCCAAGTCACATTAAAGAGAATATCCAGGTGTTTGATTTTGAATTAACACAGCACGATATGGATAACATCCTCAGCCTAAACAGGAATCTCCGACTGGCCATGTTCCCCAGAACTAAAAATCACAAAGACTATCCTTTCCACATAGAATACTGA GGACGCTTCCCC TTCCT

[0350] The aldose reductase NOV16d disclosed in this invention maps tochromosome 10.

[0351] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 358 of 361 bases(99%) identical to a gb:GENBANK-ID:BC0028621acc:BC002862.1 mRNA fromHomo sapiens (Homo sapiens, Similar to aldo-keto reductase, cloneMGC:10612 IMAGE:3941289, mRNA, complete cds)

[0352] A disclosed NOV16d polypeptide (SEQ ID NO:50) encoded by SEQ IDNO:49 has 245 amino acid residues and is presented in Table 16H usingthe one-letter code. The SignalP, Psort and/or Hydropathy resultspredict that NOV16d has no signal peptide and is likely to be localizedin the cytoplasm with a certainty of 0.4500. In an alternativeembodiment, NOV16d is likely to be localized to the lysosome (lumen)with a certainty of 0.1602, or to the microbody (peroxisome) with acertainty of 0.1369, or to the mitochondrial matrix space with acertainty of 0.1000. TABLE 16H NOV16d protein sequenceMGDIPAVGLSSWKQASPGKVTEAVKEAIDAGYRHFDCAYFYHNEREVGAGIRCKIKEGAV (SEQ IDNO:50) RREDLFIATKLWCTCHKKSLVETACRKSLKALKLNYLDLYLIHWPMGFKPRVQDLPLDESNMVIPSDTDFLDTWEAMEDLVITGLVKNIGVSNFNHEQLERLLNKPGLRFKPLTNQILIRFQIQRNVIVIPGSITPSHIKENIQVFDFELTQHDMDNILSLNRNLRLAMFPRTKNHKDYP FHIEY

[0353] The full amino acid sequence of the protein of the invention wasfound to have 109 of 110 amino acid residues (99%) identical to, and 109of 110 amino acid residues (99%) similar to, the 307 amino acid residueptnr:SPTREMBL-ACC:Q9BU71 protein from Homo sapiens (Human) (SIMILAR TOALDO-KETO REDUCTASE).

[0354] The ALDO-KETO REDUCTASE-like gene disclosed in this invention isexpressed in at least the following tissues: Adipose, Testis. Thenucleic acids and proteins of the invention have applications in thediagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: cancer, trauma,regeneration (in vitro and in vivo), viral/bacterial/parasiticinfections, systemic lupus erythematosus, autoimmune disease, asthma,emphysema, scleroderma, allergy, ARDS, infertility and other diseases aswell as other diseases, disorders and conditions.

[0355] NOV16e

[0356] A disclosed NOV16e nucleic acid of 937 nucleotides (also referredto as CG55778-05)(SEQ ID NO:51) encoding a novel Aldose Reductase-likeprotein is shown in Table 16I.

[0357] An open reading frame was identified beginning with an ATGinitiation codon at nucleotides 31-33 and ending with a TAA codon atnucleotides 838-840. Putative untranslated regions upstream from theinitiation codon and downstream from the termination codon areunderlined. The start and stop codons are in bold in Table 161. TABLE161 NOV16e nucleotide sequence GGCGGGGCGGCGGGGCGGCCGGCGGCGGCCATGGGAGATATCCCAGCCGTGGGCCTCAGC (SEQ ID NO:51)TCCTGGAAGCAGGCTTCTCCAGGGAAAGTGACCGAGGCAGTGAAAGAGGCCATTGACGCAGGGTACCGGCACTTCGACTGTGCTTACTTTTACCACAATGAGAGGGAGGTTGGAGCAGGGATCCGTTGCAAGATCAAGGAAGGCGCTGTAAGACGGGAGGATCTGTTCATTGCCACTAAGCCTCCTCATCCAGAATGGATCATGAGCTGCAGTGAACTTTCCTTCTGCCTCTCACATCCTCGAGTGCAGGACTTGCCTCTGGACGAGAGCAACATGGTTATTCCCAGTGACACGGACTTCCTGGACACGTGGGAGGCCATGGAGGACCTGGTGATCACCGGGCTGGTGAAGAACATCGGGGTGTCAAACTTCAACCATGAACAGCTTGAGAGGCTTTTGAATAAGCCTGGGTTGAGGTTCAAGCCACTAACCAACCAGATTGAGTGCCACCCATATCTTACTCAGAAGAATCTGATCAGTTTTTGCCAATCCAGAGATGTGTCCGTGACTGCTTACCGTCCTCTTGGTGGCTCGTGTGAGGGGGTTGACCTGATAGACAACCCTGTGATCAAGAGGATTGCAAAGGAGCACGGCAAGTCTCCTGCTCAGATTTTGATCCGATTTCAAATCCAGAGGAATGTGATAGTGATCCCCGGATCTATCACCCCAAGTCACATTAAAGAGAATATCCAGGTGTTTGATTTTGAATTAACACAGCACGATATGGATAACATCCTCAGCCTAAACAGGAATCTCCGACTGGCCATGTTCCCCATGTAAATATGGCTCCTTCTTTTTAAAACAGAGGGAAGAATATACAGATTGAATGATTGGTGTCTGAATAGAACTAAAAATCACAAAGACTATCCTTTCCACA

[0358] The aldose reductase NOV16e disclosed in this invention maps tochromosome 10.

[0359] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 700 of 700 bases(100%) identical to a gb:GENBANK-ID:BC0028621acc:BC002862.1 mRNA fromHomo sapiens (Homo sapiens, Similar to aldo-keto reductase, cloneMGC:10612 IMAGE:3941289, mRNA, complete cds).

[0360] A disclosed NOV16e polypeptide (SEQ ID NO:52) encoded by SEQ IDNO:51 has 269 amino acid residues and is presented in Table 16J usingthe one-letter code. The SignalP, Psort and/or Hydropathy resultspredict that NOV16e has no signal peptide and is likely to be localizedin the cytoplasm with a certainty of 0.4500. In an alternativeembodiment, NOV16e is likely to be localized to the lysosome (lumen)with a certainty of 0.1602, or to the microbody (peroxisome) with acertainty of 0.1369, or to the mitochondrial matrix space with acertainty of 0.1000. TABLE 16J NOV16e protein sequenceMGDIPAVGLSSWKQASPGKVTEAVKEAIDAGYRHFDCAYFYHNEREVGAGIRCKIKEGAV (SEQ IDNO:52) RREDLFIATKPPHPEWIMSCSELSFCLSHPRVQDLPLDESNMVIPSDTDFLDTWEAMEDLVITGLVKNIGVSNFNHEQLERLLNKPGLRFKPLTNQIECHPYLTQKNLISFCQSRDVSVTAYRPLGGSCEGVDLIDNPVIKRIAKEHGKSPAQILIRFQIQRNVIVIPGSITPSHIKENIQVFDFELTQHDMDMILSLNRNLRLAMFPM

[0361] The full amino acid sequence of the protein of the invention wasfound to have 206 of 233 amino acid residues (88%) identical to, and 211of 233 amino acid residues (90%) similar to, the 307 amino acid residueptnr:SPTREMBL-ACC:Q9BU71 protein from Homo sapiens (Human) (SIMILAR TOALDO-KETO REDUCTASE).

[0362] The ALDO-KETO REDUCTASE-like gene disclosed in this invention isexpressed in at least the following tissues: Adipose, Testis. Thenucleic acids and proteins of the invention have applications in thediagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: cancer, trauma,regeneration (in vitro and in vivo), viral/bacterial/parasiticinfections, systemic lupus erythematosus, autoimmune disease, asthma,emphysema, scleroderma, allergy, ARDS, infertility and other diseases aswell as other diseases, disorders and conditions.

[0363] NOV16a, NOV16b, NOV16c, NOV15d and NOV15e are very closelyhomologous as is shown in the amino acid alignment in Table 16K.

[0364] In a search of public sequence databases, NOV16a was found tohave homology to the amino acid sequences shown in the BLASTP datalisted in Table 16L. TABLE 16L BLASTP results for NOV16a Gene Index/Length Identity Positives Identifier Protein/Organism (aa) (%) (%)Expect ptnr:SPTREMBL- ALDO-KETO REDUCTASE 320 190/193 190/193 1.8e-159ACC:Q96JD6 LOOPADR - Homo sapiens (98%) (98%) ptnr:SPTREMBL- SIMILAR TOALDO-KETO 307 178/179 178/179 5.8e-152 ACC:Q9BU71 REDUCTASE - Homo (99%)(99%) sapiens ptnr:SPTREMBL- 18100E1I10RIK PROTEIN 301 225/302 260/3025.0e-124 ACC:Q9DCT1 (RIKEN CDNA 1810061110 (74%) (86%) GENE) - Musmusculus ptnr:SPTREMBL- ALDO-KETO 301 223/302 259/302 3.5e-123ACC:O09125 REDUCTASE - (73%) (85%) Mus musculus ptnr:SPTREMBL-1810061I10RIK PROTEIN - 276 205/274 235/274 9.8e-112 ACC:Q9D8L2 Musmusculus (74%) (85%)

[0365] Other BLAST results include sequences from the Patp database,which is a propriety database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 16M. TABLE 16M Patp BLASTP Analysis for NOV16a Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAM80263 Human protein SEQ ID NO 264 126/127126/127 6.4e-123 3909 - Homo sapiens (99%) (99%) patp:AAR15425 Humanaldose reductase - 316 180/304 226/304 1.4e-96 Homo sapiens (59%) (74%)patp:AAR06652 Placenta-specific 316 179/304 226/304 2.9e-96 protein-9 -Homo sapiens (58%) (74%) patp:AAW69357 Rat lens aldose reductase - 316178/303 221/303 3.8e-94 Rattus sp (58%) (72%) patp:AAB10871 Murine MVDPprotein - Mus 316 180/304 222/304 6.3e-92 sp (59%) (73%)

[0366] Table 16N lists the domain description from DOMAIN analysisresults against NOV16a. TABLE 16N Domain Analysis of NOV16a Pfamanalysis Model Domain seq-f seq-t hmm-f hmm-t score E-value ROK 1/1 27 43.. 1  17 [. 7.3 0.42 DNA_methylase 1/1 218 229 .. 407 418 .] 3.0 5.9aldo_ket_red 1/1 4 282 .. 9 368 .] 430.9 1.4e−127 Alignments oftop-scoring domains: ROK: domain 1 of 1, from 27 to 43: score 7.3, E= 0.42 giDlGgTkielalvded < -* (SEQ ID NO:212) +||+|++++ +|+++ + NOV16a27 AIDAGYRHFDCAYFYHN 43 DNA_methylase: domain 1 of 1, from 218 to 229:score 3.0, E = 5.9 pvaeaIakeikk < -* (SEQ ID NO:213) ||+++||||++| NOV16a218 PVIKRIAEERGK 229 aldo_ket_red: domain 1 of 1, from 4 to 282: score430.9, E = 1.4e-127 mPllGlGtwqtpgeedylwgrvdkeeakeaVkaAldaGYRhiDtAai (SEQID NO: 214) +|++||  |+          +++++ + ||||+|+||||||+|+|++ NOV16a 4IPAVGLSSWK----------QASPGKVTEAVKEAIDAGYRHFDCAYF 40YgNGqkPgqSEeevGeaikealeegsvvvitkykRediFitsdKlwntfg|+|       |+|||++|+ ++ ||  |      |||+|| + |||+| 41YHN-------EREVGAGIRCKIKEG-AV-----RREDLFIAT-KLWCTC- 75pDlseyghspkhvrealekSLkrLgLdYVDLyLiHwPdPfkpgiedkypl       | + +|+ |++|||| |+| |+||||||||++|||    +++ 76-------HKKSLVETACRKSLEALKLNYLDLYLIHWPMGFKPR--VQDL- 115gfptdddgkliyedvpieetWkAleklvdeGkvrsIGVSNfsaeqleell  | |+ + +|+ |+++++||+|+|+|| +|+|+ ||||||++||||+|| 116--PLDESNMVIPSDTDFLDTWEAMEDLVITGLVENIGVSNFNHEQLERLL 163syagklklipPvvnQvElHPylrqdelrkvPLLpfCkshGIavtAySPLg+++| |+ ++| +||+|+||||+|+ |+      ||+| ++ |||| ||| 164NKPG-LR-FKPLTNQIECHPYLTQKNLIS-----FCQSRDVSVTAYRPLG 206sGlLtGkykteedipgdrrsllgadkgwselgspelledpvlkaiAekyg+ +                  +|            | ++||+|+||+++| 207GSS------------------EG----------VDLIDNPVIKRIAKEHG 228ykdktpAQvaLrWalqrGgGagvvvvIPKSsnpeRikeNlkafddfeLte   |+|||+++|+++||+     |+|||+| +|++||||+++| |||||+ 229---KSPAQILIRFQIQRN-----VIVIPGSITPSHIKENIQVF-DFELTQ 269 edmkaideldrgk< -*  ||+ | +|+|+ 270 HDMDNILSLNRNL 282

[0367] In a search of public sequence databases, NOV16b was found tohave homology to the amino acid sequences shown in the BLASTP datalisted in Table 16O. TABLE 16O BLASTP results for NOV16b Posi- GeneIndex/ Length Identity tives Identifier Protein/Organism (aa) (%) (%)Expect ptnr:SPTREMBL- SIMILAR TO ALDO-KETO 307 197/207 200/207 1.4e-105ACC:Q9BU71 REDUCTASE - Homo (95%) (96%) sapiens ptnr:SPTREMBL- ALDO-KETOREDUCTASE 320 197/207 200/207 1.4e-105 ACC:Q9GJD6 LOOPADR - Homo sapiens(95%) (96%) ptnr:SPTREMBL- 1810061I10RIK PROTEIN 301 82/110 93/1104.3e-91 ACC:Q9DCT1 (RIKEN CDNA 1810061I10 (74%) (84%) GENE) - Musmusculus ptnr:SPTREMBL- ALDO-KETO 301 81/110 93/110 3.0e90 ACC:O09125REDUCTASE - (73%) (84%) Mus musculus ptnr:SPTRENBL- 1810061I10RIKPROTEIN - 276 82/110 93/110 2.9e-86 ACC:Q9D8L2 Mus musculus (74%) (84%)

[0368] Other BLAST results include sequences from the Patp database,which is a propriety database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 16P. TABLE 16P Patp BLASTP Analysis for NOV16b Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAM79279 Human protein SEQ ID NO 263 246/251247/251 3.0e-133 1941 - Homo sapiens (98%) (98%) patp:AAM80263 Humanprotein SEQ ID NO 264 195/207 198/207 1.2e-104 3909 - Homo sapiens (94%)(95%) patp:AAR15425 Human aldose reductase - 316 68/107 84/107 1.1e-73Homo sapiens (63%) (78%) patp:AAR06652 Placenta-specific 316 67/10784/107 2.3e-73 protein-9 - Homo sapiens (62%) (78%) patp:AAW69357 Ratlens aldose reductase - 316 66/107 84/107 2.9e-73 Rattus sp (61%) (78%)

[0369] Table 16Q lists the domain description from DOMAIN analysisresults against NOV16b. TABLE 16Q Domain Analysis of NOV16b Pfamanalysis Model Domain seq-f seq-t hmm-f hmm-t score E-value ROK 1/1 27 43 .. 1  17 [. 7.3 0.42 aldo_ket_red 1/3 4 110 .. 9 147 .. 154.14.1e−45 aldo_ket_red 2/3 135 196 .. 158 221 .. 72.2 9.9e−21 aldo_ket_red3/3 197 244 .. 315 368 .] 67.7 2.2e−19 Alignments of top-scoringdomains: ROK: domain 1 of 1, from 27 to 43: score 7.3, E = 0.42 (SEQ IDNO:215) giDlGgTkielalvded < -* +||+|++++ +|+++ + NOV16b 27AIDAGYRHFDCAYFYHN 43 aldo_ket_red: domain 1 of 3, from 4 to 110: score154.1, E = 4.1e−45 (SEQ ID NO:216)mPllGlGtwqtpgeedylwgrvdkeeakeavkaAldaGYRhiDtAai+|++||  |+          +++++ + ||||+|+||||||+|+|++ NOV16b 4IPAVGLSSWK----------QASPGKVTEAVKEAIDAGYRHFDCAYF 40YgNGqkPgqSEeevGeaikealeegsvvvitkykRediFitsdKlwntfg|+|       |+|||++|+ ++ ||  |      |||+|| + |||+| 41YHN-------EREVGAGIRCKIKEG-AV-----RREDLFIAT-KLWCTC- 75pDlseyghspkhvrealekSLkrLgLdYvDLyLiHwPdpfkp < -*       | + +|+ |++| || |+| |+||||||||++||| 76-------HKKSLVETACRKGLKALKLNYLDLYLIHWPMGFKP 110 aldo_ket_red: domain 2 of3, from 135 to 196: score 72.2, E = 9.9e−21 (SEQ ID NO:217)ptdddgkliyedvpieetWkAleklvdeGkvrsIGVSNfsaeqleel| |+ + +|+ |+++++||+|+|+|| +|+|+ ||||||++||||+| NOV16b 135PLDESNMVIPSDTDFLDTWEAMEDLVITGLVKNIGVSNFNHEQLERL 181 lsyagklklipPvvnQv< -* |+++| |+ ++| +||+ 182 LNKPG-LR-FKPLTNQI 196 aldo_ket_red: domain 3of 3, from 197 to 244: score 67.7, E = 2.2e−19 (SEQ ID NO:218)aLrWalqrGgGagvvvvIPKSsnpeRikeNlkafddfeLteedmkai++|+++||+     |+|||+| +|++||||+++| |||||+ ||+ | NOV16b 197LIRFQIQRN-----VIVIPGSITPSHIKENIQVF-DFELTQHDMDNI 237 deldrgk < -*  +|+|+238 LSLNRNL 244

[0370] The aldo-keto reductase family includes a number of relatedmonomeric NADPH-dependent oxidoreductases, such as aldehyde reductase,aldose reductase, prostaglandin F synthase, xylose reductase, rhocrystallin, and many others. All possess a similar structure, with abeta-alpha-beta fold characteristic of nucleotide binding proteins. Thefold comprises a parallel beta-8/alpha-8-barrel, which contains a novelNADP-binding motif. The binding site is located in a large, deep,elliptical pocket in the C-terminal end of the beta sheet, the substratebeing bound in an extended conformation. The hydrophobic nature of thepocket favours aromatic and apolar substrates over highly polar ones.

[0371] Binding of the NADPH coenzyme causes a massive conformationalchange, reorienting a loop, effectively locking the coenzyme in place.This binding is more similar to FAD- than to NAD(P)-bindingoxidoreductases. This indicates that the sequence of the invention hasproperties similar to those of other proteins known to containthis/these domain(s) and similar to the properties of these domains.

[0372] The aldo-keto reductase family includes a number of relatedmonomeric NADPH-dependent oxidoreductases, such as aldose reductase,prostaglandin F synthase, xylose reductase, aldehyde reductases,hydroxysteroid dehydrogenases, dihydrodiol dehydrogenases and manyothers. All possess a similar structure, with a beta-alpha-beta foldcharacteristic of nucleotide binding proteins. The fold comprises aparallel beta-8/alpha-8-barrel, which contains a novel NADP-bindingmotif. The (alpha/beta)8-barrel fold provides a common scaffold for anNAD(P)(H)-dependent catalytic activity, with substrate specificitydetermined by variation of loops on the C-terminal side of the barrel.All the aldo-keto reductases are dependent on nicotinamide cofactors forcatalysis and retain a similar cofactor binding site, even amongproteins with less than 30% amino acid sequence identity. See Jez J M,et al., Biochem J Sep. 15, 1997;326 (Pt 3):625-36. Rabbit aldosereductase, which catalyzes the conversion of glucose to sorbitol (anorganic osmolyte), is induced in renal medullary cells underhyperosmotic conditions. See Ferraris J D, et al., Proc. Natl. Acad.Sci. USA Oct. 25, 1994;91(22):10742-6.

[0373] NOV17

[0374] A disclosed NOV17 nucleic acid of 884 nucleotides (also referredto as CG55982-01) (SEQ ID NO:53) encoding a novel apolipoproteinA-I-like protein is shown in Table 17A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 87-89and ending with a TGA codon at nucleotides 807-809. Putativeuntranslated regions are found upstream from the initiation codon anddownstream from the termination codon, and are underlined. The start andstop codons are shown in bold in Table 17A. TABLE 17A NOV17 nucleotidesequence GAATTCAAAAAAAAAAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGAGAGACTGCGAG(SEQ ID NO:53) AAGGAGGTCCCCCACGGCCCTTCAGGATGAAAGCTGCGGTGCTGACCTTGGCCGTGCTCTTCCTGACGGGGAGCCAGGCTCGGCATTTCTGGCAGCAAGATGAACCCCCCCAGAGCCCCTGGGATCGAGTGAAGGACCTGGCCACTGTGTACGTGGATGTGCTCAAAGACAGCGTGACCTCCACCTTCAGCAAGCTGCGCGAACAGCTCGGCCCTGTGACCCAGGAGTTCTGGGATAACCTGGAAAAGGAGACAGAGGGCCTGAGGCAGGAGATGAGCAAGGATCTGGAGGAGGTGAAGGCCAAGGTGCAGCCCTACCTGGACGACTTCCAGAAGAAGTGGCAGGAGGAGATGGAGCTCTACCGCCAGAAGGTGGAGCCGCTGCGCGCAGAGCTCCAAGAGGGCGCGCGCCAGAAGCTGCACGAGCTGCAAGAGAAGCTGAGCCCACTGGGCGAGGAGATGCGCGACCGCGCGCGCGCCCATGTGGACGCGCTGCGCACGCATCTGGCCCCCTACAGCGACGAGCTGCGCCAGCGCTTGGCCGCGCGCCTTGAGGCTCTCAAGGAGAACGGCGGCGCCAGACTGGCCGAGTACCACGCCAAGGCCACCGAGCATCTGAGCACGCTCAGCGAGAAGGCCAAGCCCGCGCTCGAGGACCTCCGCCAAGGCCTGCTGCCCGTGCTGGAGAGCTTCAAGGTCAGCTTCCTGAGCGCTCTCGAGGAGTACACTAAGAAGCTCAACACCCAGTGA GGCGCCCGCCGCCGCCCCCCTTCCCGGTGCTCAGATAAACGTTTCCAAAGTGGGAAAAAAAAAAAAAAGAATTC

[0375] The apolipoprotein A-I-like NOV17 disclosed in this inventionmaps to the long arm of chromosome 11.

[0376] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 637 of 637 bases(100%) identical to a gb:GENBANK-ID:HUMAPOAIB|acc:M27875.1 mRNA fromHomo sapiens (Human apolipoprotein A-I mRNA, complete cds).

[0377] A disclosed NOV17 polypeptide (SEQ ID NO:54) encoded by SEQ IDNO:53 240 amino acid residues and is presented in Table 17B using theone-letter code. The SignalP, Psort and/or Hydropathy results predictthat NOV17 has a signal peptide and is likely to be localizedextracellularly with a certainty of 0.3700, as expected by a member ofthe apolipoprotein A1/A4/E family. In an alternative embodiment, NOV17is likely to be localized to the endoplasmic reticulum (membrane) with acertainty of 0.1000, or to the endoplasmic reticulum (lumen) with acertainty of 0.1000, or to the microbody (peroxisome) with a certaintyof 0.1000. Most likely cleavage site for the signal peptide is betweenamino acids 18 and 19, i.e., at the dash in the sequence SQA-RH. TABLE17B NOV17 protein sequenceMKAAVLTLAVLFLTGSQARHFWQQDEPPQSPWDRVKDLATVYVDVLKDSVTSTFSKLREQ (SEQ IDNO:54) LGPVTQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARAHVDALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ

[0378] The full amino acid sequence of the protein of the invention wasfound to have 193 of 193 amino acid residues (100%) identical to, and193 of 193 amino acid residues (100%) similar to, the 267 amino acidresidue ptnr:SWISSPROT-ACC:P02647 protein from Homo sapiens (Human)(APOLIPOPROTEIN A-I PRECURSOR (APO-AI))(FIG. 3B). The sequence of thisinvention lacks 27 internal amino acids when compared toptnr:SWISSPROT-ACC:P02647 protein from Homo sapiens (Human)(APOLIPOPROTEIN A-I PRECURSOR (APO-AI)).

[0379] In a search of public sequence databases, NOV17 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 17C. TABLE 17C BLASTP results for NOV17 Posi- Gene Index/ LengthIdentity tives Identifier Protein/Organsim (aa) (%) (%) Expectptnr:SWISSPROT- Apolipoprotein A-I 267 193/193 193/193 9.5e-98ACC:P02647 precursor (Apo-AI) - (100%) (100%) Homo sapiensptnr:TREMBLNEW- APOA1 PROTEIN - Homo 249 193/193 193/193 9.5e-98ACC:AAA51747 sapiens (100%) (100%) ptnr:REMTREMBL- APOA1 PROTEIN - Homo243 193/193 193/193 9.5e-98 ACC:CAA00975 sapiens (100%) (100%)ptnr:REMTREMBL- SEQUENCE 10 FROM 200 192/193 192/193 6.7e-97ACC:CAA03490 PATENT W09G37608 - (99%) (99%) unidentified ptnr:SWISSPROT-Apolipoprotein A-I 267 186/193 189/193 3.8e-94 ACC:P15568 precursor(Apo-AI) - (96%) (97%) Macaca fascicularis (Crab eating macaque)(Cynomolgus monkey)

[0380] A multiple sequence alignment is shown in Table 17D, with theprotein of the invention being shown on the first line in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 17C.

[0381] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 17E. TABLE 17E Patp BLASTP Analysis for NOV17 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAP61079 Assumed human 267 193/193 193/1937.3e-98 apolipoprotein A-1 (100%) (100%) derivative gene product - Homosapiens patp:AAP82128 Entire human 267 193/193 193/193 7.3e-98preproapoprotein A1 - (100%) (100%) synthetic patp:AAR34032 Sequence ofapo AI - 267 193/193 193/193 7.3e-98 Homo sapiens (100%) (100%)patp:AAR72705 Human apo A-I including 267 193/193 193/193 7.3e-98 signaland propeptide (100%) (100%) sequences - Homo sapiens patp:AAY18675Human apolipoprotein AI 267 193/193 193/193 7.3e-98 protein sequence -Homo (100%) (100%) sapiens

[0382] TABLE 17F Domain Analysis of NOV17 Pfam analysis Model Domainseq-f seq-t hmm-f hmm-t score E-value KMP11 1/1 38 130 .. 1  90 [] −6.77.5 Apolipoprotein 1/1 2 238 .. 1 277 [] 376.2 3.3e−109 Alignments oftop-scoring domains: KMP11: domain 1 of 1, from 38 to 130: score −6.7, E= 7.5 (SEQ ID NO:224) mAttyEeFaaKLDRLDeEFnkKmeEq...nakFFAdKPDest..LsP+|| | +     | +   |  |++|| ++  + | |  +  |++| NOV17 38LATVYVDVLK--DSVTSTFS-KLREQlgpVTQEFWDNLEKETegLRQ 81EmKEHYEKFEkmiqEHtdKFnKKmrEHsEHFKqKFAEL.LEqqKnAqyP <||    |     +|   | | || +|  | ++||   |+ | |  | 82EMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQKVEPLrAELQEGARQK 130 Apolipoprotein:domain 1 of 1, from 2 to 238: score 376.2, E = 3.3e−109 (SEQ ID NO:225)KalvlaLalllLtGcqArsfwQadePEvteqaWqqsqwdqvkdrfwv||+||+||+|+|||+|||+|||+|||+       ||+||+|||+++| NOV17 2KAAVLTLAVLFLTGSQARHFWQQDEPP-------QSPWDRVKDLATV 41YlrqVkdssdqaveqLessqvtqeLnllLednldelksyaeeLqeqLgPv|++ +|||                           + |++++|+|||||| 42YVDVLKDS---------------------------VTSTFSKLREQLGPV 64aqefqarLsKetqalraelgkDlEdvrnrlaPyrdEvqamlgqnleeyRq+|||+++|+|||+ ||+|+ ||||+|+++++||+|++|+++++++| ||| 65TQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQ 114rLePlareLrkrlrrdaeeLqkrLaPyaeelReraernVdalrerLgPyv++||| +||++++|++++|||++|+|++||+|+||+++|||||++|+||+ 115KVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARARVDALRTHLAPYS 164EqlRqkaAtlltqrleeLrEraqpyaeEykeqleeqlselReklapvred++|||+    |++|||+|+|++ ++++||++++ |+||+| ||++|++|| 165DELRQR----LAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALED 210lqevltpvlEqaQlklqaeafqeelkkkle < -* |+++| ||||+  +|+++++++||+ |||+ 211LRQGLLPVLES--FKVSFLSALEEYTKKLN 238

[0383] The apolipoprotein A-I disclosed in this invention is expressedin at least the following tissues: adrenal gland, bone marrow,brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantianigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetalliver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland,pancreas, pituitary gland, placenta, prostate, salivary gland, skeletalmuscle, small intestine, spinal cord, spleen, stomach, testis, thyroid,trachea, uterus, Colon, Gall Bladder, Liver, Lung, Lymph node, Lymphoidtissue, Ovary, Spleen, Thymus, Whole Organism. This information wasderived by determining the tissue sources of the sequences that wereincluded in the invention including but not limited to SeqCallingsources, Public EST sources, literature sources, and/or RACE sources.

[0384] In addition, the sequence is predicted to be expressed in liverbecause of the expression pattern of (GENBANK-ID:gb:GENBANK-ID:HUMAPOAIB|acc:M27875.1) a closely related Humanapolipoprotein A-I mRNA, complete cds homolog in species Homo sapiens.

[0385] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention may have efficacy fortreatment of patients suffering from: atherosclerosis, coronary arterydisease, other arterial diseases and other diseases, disorders andconditions of the like. The structure of Tangier APOA-I, which fails toassociate with HDL, corresponds to that of PRO-APOA-I. This suggeststhat a faulty conversion of the precursor molecule is responsible forits formation. Tangier disease is characterized by an absence of plasmaHDL and accumulation of cholesteryl esters. Milano variant patients havevariable amounts of normal versus variant APOA-I, decreasedconcentrations of HDL, and moderate increases in truglycerides, but noevidence of premature vascular disease. A sequence variant has beenidentified in amyloid fibrils from patients with polyneuropathicamyloidosis type III (FAP III): the Iowa type variant. Variant ARG-84causes autosomal dominant amyloidosis. Defects in APOAI can be the causeof hereditary non-neuropathic systemic amyloidosis (Ostertag-type).

[0386] The inverse relationship between high density lipoprotein (HDL)plasma levels and coronary heart disease has been attributed to the rolethat HDL and its major constituent, apolipoprotein A-I (apoA-I), play inreverse cholesterol transport (RCT). The efficiency of RCT depends onthe specific ability of apoA-I to promote cellular cholesterol efflux,bind lipids, activate lecithin:cholesterol acyltransferase (LCAT), andform mature HDL that interact with specific receptors and lipid transferproteins. From the intensive analysis of apoA-I secondary structure hasemerged our current understanding of its different classes ofamphipathic alpha-helices, which control lipid-binding specificity. Twomodels are considered for discoidal lipoproteins formed by associationof two apoA-1 with phospholipids. In the first or picket fence model,each apoA-I wraps around the disc with antiparallel adjacentalpha-helices and with little intermolecular interactions. In the secondor belt model, two antiparallel apoA-I are paired by their C-terminalalpha-helices, wrap around the lipoprotein, and are stabilized bymultiple intermolecular interactions. While recent evidence supports thebelt model, other models, including hybrid models, cannot be excluded.ApoA-I alpha-helices control lipid binding and association with varyinglevels of lipids. The N-terminal helix 44-65 and the C-terminal helix210-241 are recognized as important for the initial association withlipids. In the central domain, helix 100-121 and, to a lesser extent,helix 122-143, are also very important for lipid binding and theformation of mature HDL, whereas helices between residues 144 and 186contribute little. The LCAT activation domain has now been clearlyassigned to helix 144-165 with secondary contribution by helix 166-186.The lower lipid binding affinity of the region 144-186 may be importantto the activation mechanism allowing displacement of these apoA-Ihelices by LCAT and presentation of the lipid substrates. No specificsequence has been found that affects diffusional efflux to lipid-boundapoA-I. In contrast, the C-terminal helices, known to be important forlipid binding and maintenance of HDL in circulation, are also involvedin the interaction of lipid-free apoA-I with macrophages and specificlipid efflux. Epidemiological and clinical studies showing anassociation between decreased concentrations of high-density lipoprotein(HDL) cholesterol and increased risk of premature coronary arterydisease have generated interest in the mechanism through which HDLprevents atherosclerosis. Recognition of the importance ofapolipoproteins (apo(s)) has led to the separation of HDL intosubpopulations according to their apolipoprotein composition. It is nowrecognised that HDL comprises at least two types of apo A-I-containinglipoproteins: LpA-I:A-II containing both apo A-I and apo A-II and LpA-Icontaining apo A-I but not apo A-II. A majority of studies support thefact that LpA-I is more effective than LpA-I:A-II in promoting cellularcholesterol efflux, the first step in reverse cholesterol transport.Studies in transgenic animals have revealed that the gene transfer ofhuman apo A-I in mice and rabbits increases plasma apo A-I and HDLcholesterol levels and particularly apo A-I-rich HDL particleconcentrations, leading to inhibition of the development of dietary orgenetically induced atherosclerosis. On the other hand, gene transfer ofapo A-II in mice gives conflicting results. The conclusions of someexperiments indicate either an atherogenic, or a poorlyanti-atherogenic, or even a strongly anti-atherogenic role for apo A-IIand for apo A-II-rich HDL lipoproteins. Although these experimentalresults have been obtained in animals, they confirm previous studiesobtained in human clinical studies, indicating that apo A-I-rich HDL(tested as LpA-I in clinical studies) are generally strong plasmamarkers of atherosclerosis protection while the clinical significance ofapo A-I+apo A-II HDL (tested as LpA-I:A-II in clinical studies) is morecontroversial. Over the past few years, new experimental approaches havereinforced the awareness among investigators that the heterogeneity ofHDL particles indicates significant differences in production andcatabolism of HDL particles. Recent kinetic studies have suggested thatsmall HDL, containing two apolipoprotein A-I molecules per particle, areconverted in a unidirectional manner to medium HDL or large HDL,containing three or four apolipoprotein A-I molecules per particle,respectively. Conversion appears to occur in close physical proximitywith cells and not while HDL particles circulate in plasma. The mediumand large HDL are terminal particles in HDL metabolism with large HDL,and perhaps medium HDL, being catabolized primarily by the liver. Thesekinetic studies of HDL subfraction metabolism are compelling in-vivodata that are consistent with the proposed role of HDL in reversecholesterol transport. The protein components of human lipoproteins,apolipoproteins, allow the redistribution of cholesterol from thearterial wall to other tissues and exert beneficial effects on systemsinvolved in the development of arterial lesions, like inflammation andhemostasis. Because of these properties, the antiatherogenicapolipoproteins, particularly apo A-I and apo E, may provide aninnovative approach to the management of vascular diseases. The recentavailability of extractive or biosynthetic molecules is allowing adetailed overview of their therapeutic potential in a number of animalmodels of arterial disease. Infusions of apo E, or more dramatically, ofapo A-I, both recombinant or extractive, cause a direct reduction of theatherosclerotic burden in experimental animals. Naturally, as the apoA-I(Milano) (apo A-I(M)) dimer, or engineered recombinantapolipoproteins with prolonged permanence in plasma and improvedfunction may offer an even better approach to the therapeutic handlingof arterial disease. This progress will go on in parallel withinnovations in the technologies for direct, non invasive assessments ofhuman atherosclerosis, thus allowing closer monitoring of this potentialnew approach to therapy.

[0387] NOV18

[0388] A disclosed NOV18 nucleic acid of 751 nucleotides (also referredto as CG56747-02) (SEQ ID NO:55) encoding a novel Apolipoprotein A-1Precursor-like protein is shown in Table 18A. An open reading frame wasidentified beginning with an ATG initiation codon at nucleotides 87-89and ending with a TGA codon at nucleotides 708-710. Putativeuntranslated regions are found upstream from the initiation codon anddownstream from the termination codon, and are underlined. The start andstop codons are in bold in Table 18A. TABLE 18A NOV18 nucleotidesequence GAATTCAAAAAAAAAAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGAGAGACTGCGAG(SEQ ID NO:55) AAGGAGGTCCCCCACGGCCCTTCAGGATGAAAGCTGCGGTGCTGACCTTGGCCGTGCTCTTCCTGACGGGGAGCCAGGCTCGGCATTTCTGGCAGCAAGATGAACCCCCCCAGAGCCCCTGGGATCGAGTGAAGGACCTGGCCACTGTGTACGTGGATGTGCTCAAGGACAGCGTGACCTCCACCTTCAGCAAGCTGCGCGAACAGCTCGGCCCTGTGACCCAGGAGTTCTGGGATAACCTGGAAAAGGAGACAGAGGGCCTGAGGCAGGAGATGAGCAAGGATCTGGAGGAGGTGAAGGCCAAGGTGCAGCCCTACCTGGACGACTTCCAGAAGAAGTGGCAGGAGGAGATGGAGCTCTACCGCCAGAAGGTGGAGCCGCTGCGCGCAGAGCTCCAAGAGGGCGCGCGCCAGAAGCTGCACGAGCTGCGCCAGCGCTTGGCCGAGCGCCTTGAGGCTCTCAAGGAGAACGGCGGCGCCAGACTGGCCGAGTACCACGCCAAGGCCACCGAGCATCTGAGCACGCTCAGCGAGAAGGCCAAGCCCGCGCTCGAGGACCTCCGCCAAGGCCTGCTGCCCGTGCTGGAGAGCTTCAAGGTCAGCTTCCTGAGCGCTCTCGAGGAGTACACTAAGAAGCTCAACACCCAGTGA GGCGCCCGCCGCCGCCCCCCTTCCCGGTGCTCAGAATAAAC

[0389] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 424 of 521 bases(81%) identical to a gb:GENBANK-ID:HSAPOAIT|acc:X07496.1 mRNA from Homosapiens (Human Tangier apoA-I gene).

[0390] A disclosed NOV18 polypeptide (SEQ ID NO:56) encoded by SEQ IDNO:55 has 207 amino acid residues and is presented in Table 18B usingthe one-letter code. NOV18 polypeptides are likely Type IIIb (Nexo Ccyt)membrane proteins. The SignalP, Psort and/or Hydropathy results predictthat NOV18 has a signal peptide and is likely to be localizedextracellularly with a certainty of 0.3700. In an alternativeembodiment, NOV18 is likely to be localized to the microbody(peroxisome) with a certainty of 0.1129, or to the endoplasmic reticulummembrane with a certainty of 0.1000, or to the endoplasmic reticulum(lumen) with a certainty of 0.1000. The signal peptide is predicted bySignalP to be cleaved between amino acids 18 and 19, i.e., at the dashin the sequence SQA-RH. TABLE 18B NOV18 protein sequenceMKAAVLTLAVLFLTGSQARHFWQQDEPPQSPWDRVKDLATVYVDVLKDSVTSTFSKLREQ (SEQ IDNO:56) LGPVTQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELRQRLAERLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ

[0391] NOV18 is an internal splice variant of the previously identifiedsequence NOV17 (Accession Number CG55982-01). The relationship betweenthe NOV17 and NOV18 protein sequences is shown in Table 18C.

[0392] The full amino acid sequence of the NOV18 protein of theinvention was found to have 104 of 156 amino acid residues (66%)identical to, and 118 of 156 amino acid residues (75%/O) similar to, the267 amino acid residue ptnr:SWISSPROT-ACC:P02647 protein from Homosapiens (Human) (APOLIPOPROTEIN A-I PRECURSOR (APO-AI)).

[0393] In a search of public sequence databases, NOV18 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 18D. TABLE 18D BLASTP results for NOV18 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SWISSPROT- Apolipoprotein A-I 267 104/156 118/156 3.8e- ACC:P02647precursor (Apo-AI) - (66%) (75%) 46 Homo sapiens ptnr:TREMBLNEW- APOA1PROTEIN - Homo 249 104/156 118/156 3.8e- ACC:AAA51747 sapiens (66%)(75%) 46 ptnr:REMTREMBL- APOA1 PROTEIN - Homo 243 104/156 118/156 3.8e-ACC:CAA00975 sapiens (66%) (75%) 46 ptnr:REMTREMBL- SEQUENCE 10 FROM 200105/156 119/156 1.0e- ACC:CAA03490 PATENT W09637608 - (67%) (76%) 45unidentified ptnr:SWISSPROT- Apolipoprotein A-I 267 104/156 112/1562.4e- ACC:P15568 precursor (Apo-AI) - (66%) (71%) 44 Macaca fascicularis(Crab eating macaque) (Cynomolgus monkey)

[0394] A multiple sequence alignment is shown in Table 18E, with theprotein of the invention being shown on the first line in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 18D.

[0395] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 18F. TABLE 18F Patp BLASTP Analysis for NOV18 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp:AAP61079 Assumed human 261 104/156 118/1563.0e-46 apolipoprotein A-1 (66%) (75%) derivative gene product - Homosapiens patp:AAP82128 Entire human 267 104/156 118/156 3.0e-46preproapoprotein A1 - (66%) (75%) synthetic patp:AAR34032 Sequence ofapo A1 - 267 104/156 118/156 3.0e-46 Homo sapiens (66%) (75%)patp:AAR72705 Human apo A-I including 267 104/156 118/156 3.0e-46 signaland propeptide (66%) (75%) sequences - Homo sapiens patp:AAY18675 Humanapolipoprotein AI 267 104/156 118/156 3.0e-46 protein sequence - Homo(66%) (75%) sapiens

[0396] Table 18G lists the domain description from DOMAIN analysisresults against NOV18. TABLE 18G Domain Analysis of NOV18 Pfam analysisModel Domain seq-f seq-t hmm-f hmm-t score E-value KMP11 1/1 38 130 .. 1 90 [] −6.7 7.5 Apolipoprotein 1/1 2 205 .. 1 277 [] 256.2 4.4e−73Alignments of top-scoring domains: KMP11: domain 1 of 1, from 38 to 130:score −6.7, E = 7.5 (SEQ ID NO:231)mAttyEeFaaKLDRLDeEFnkKmeEq...nakFFADKPDest..LsP+|| | +     | +   |  |++|| ++  + | |  +  |++| NOV18 38LATVYVDVLK--DSVTSTFS-KLREQlgpVTQEFWDNLEKETegLRQ 81EmKEHYEKFEkmiqEHtdKFnKKmrEHSEHFKqKFAEL.LEqqKnAqyP <||    |     +|   | | || +|  | ++||   |+ | |  | 82EMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQKVEPLrAELQEGARQK 130 Apolipoprotein:domain 1 of 1, from 2 to 205: score 256.2, E = 4.4e−73 (SEQ ID NO:232)KalvlaLalllLtGcqArsfwQadePEvteqaWqqSqwdqvkdrfwv||+||+||+|+|||+|||+|||+|||+       ||+||+|||+++| NOV18 2KAAVLTLAVLFLTGSQARHFWQQDEPP-------QSPWDRVKDLATV 41YlrqVkdssdqaveqLessqvtqeLnllLednldelksyaeeLqeqLgPv|++ +|||                           + |++++|+|||||| 42YVDVLKDS---------------------------VTSTFSKLREQLGPV 64aqefqarLsKetqalraelgkDlEdVrnrlaPyrdEvqamlgqnleeyRq+|||+++|+|||+ ||+|+ ||||+|+++++||+|++|+++++++| ||| 65TQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQ 114rLePlareLrkrlrrdaeeLqkrLaPyaeelReraernVdalrerLgPyv ++||| +||++++|++++||115 KVEPLRAELQEGARQKLHEL------------------------------ 134EqlRqkaAtlltqrleeLrEraqpyaeEykeqleeqlselReklapVred   ||+    |++|||+|+|++ ++++||++++ |+||+| ||++|++|| 135---RQR----LAERLEALKENGGARLAEYHAKATEHLSTLSEKAKPALED 177lqevltpvlEqaQlklqaeafqeelkkkle <-* |+++| ||||+  +|+++++++||+ |||+ 178LRQGLLPVLES--FKVSFLSALEEYTKKLN 205

[0397] IPR000074: Human apolipoprotein E, a blood plasma protein,mediates the transport and uptake of cholesterol and lipid by way of itshigh affinity interaction with different cellular receptors, includingthe low-density lipoprotein (LDL) receptor. The three-dimensionalstructure of the LDL receptor-binding domain of apoE indicates that theprotein forms an unusually elongated four-helix bundle that may bestabilized by a tightly packed hydrophobic core that includes leucinezipper-type interactions and by numerous salt bridges on the mostlycharged surface. Basic amino acids important for LDL receptor bindingare clustered into a surface patch on one long helix.

[0398] The sequence is predicted to be expressed in the followingtissues because of the expression pattern of (GENBANK-ID:gb:GENBANK-ID:HSAPOAIT|acc:X07496.1) a closely related Human TangierapoA-I gene homolog in species Homo sapiens:lymphocyte.

[0399] The nucleic acids and proteins of the invention have applicationsin the diagnosis and/or treatment of various diseases and disorders. Forexample, the compositions of the present invention will have efficacyfor the treatment of patients suffering from: dysbetalipoproteinemia,hyperlipoproteinemia type III, atherosclerosis, xanthomatosis andpremature coronary and/or peripheral vascular disease, hypothyroidism,systemic lupus erythematosus, diabetic acidosis, hypercholesterolemia,planar and tendon xanthomas, dysbetalipoproteinemia,hypercholesterolemia, premature cardiovascular disease, acceleratedvascular disease, Alzheimer Disease, familial amyloidoticpolyneuropathy, Down syndrome and other neurological disorders as wellas other diseases, disorders and conditions.

[0400] Utermann et al. (Clin. Genet. 15: 63-72, 1979) described 2phenotypes, apoE(IV+) and apoE(IV−), differentiated by analyticalisoelectric focusing. They concluded that this polymorphism ofapolipoprotein E in human serum is determined by 2 autosomal codominantalleles, apoE(n) and apoE(d). Homozygosity for the latter results inprimary dysbetalipoproteinemia but only some persons develop grosshyperlipidemia (hyperlipoproteinemia type III). Vertical transmission ispseudodominance due to high frequency of the apoE(d) gene (Utermann etal., 1979). Dysbetalipoproteinemia is already expressed in childhood.They concluded that primary dysbetalipoproteinemia is a frequentmonogenic variant of lipoprotein metabolism, but not a disease.Coincidence of the genes for this dyslipoproteinemia with any of thegenes for monogenic or polygenic forms of familial hyperlipemia resultsin hyperlipoproteinemia type III. Further complexities of the geneticsof the apolipoprotein E system were discussed by Utermann et al. (Am. J.Hum. Genet. 32: 339-347, 1980). Apolipoprotein E (apoE) of very lowdensity lipoprotein (VLDL) from different persons shows 1 of 2 complexpatterns, termed alpha and beta (Zannis et al., 1981). Three subclassesof each pattern were found and designated alpha-II, alpha-III andalpha-IV and beta-II, beta-III and beta-IV. From family studies, Zanniset al. (Am. J. Hum. Genet. 33: 11-24, 1981) concluded that a singlelocus with 3 common alleles is responsible for these patterns. Thealleles were designated epsilon-II, -III, and -IV. The authors furtherconcluded that beta class phenotypes represent homozygosity for one ofthe epsilon alleles, e.g., beta-II results from homozygosity for theepsilon-II allele. In contrast, the alpha phenotypes are thought torepresent compound heterozygosity, i.e., heterozygosity for 2 differentepsilon alleles: alpha II from epsilon II and III; alpha III fromepsilon III and IV. The frequency of the epsilon II, III, and IV alleleswas estimated at 0.11, 0.72, and 0.17, respectively. ApoE subclassbeta-IV was found to be associated with type III hyperlipoproteinemia.Rall et al. (J. Biol. Chem. 257: 4171-4178, 1982) published the fullamino acid sequence. Mature apoE is a 299-amino acid polypeptide.

[0401] The 3 major isoforms of human apolipoprotein E (apoE2, -E3, and-E4), as identified by isoelectric focusing, are coded for by 3 alleles(epsilon 2, 3, and 4). The E2 (107741.0001), E3 (107741.0015), and E4(107741.0016) isoforms differ in amino acid sequence at 2 sites, residue112 (called site A) and residue 158 (calledsite B). At sites A/B, apoE2,-E3, and -E4 contain cysteine/cysteine, cysteine/arginine, andarginine/arginine, respectively (Weisgraber et al., J. Biol. Chem. 256:9077-9083, 1981; Rall et al., Proc. Nat. Acad. Sci. 79: 4696-4700,1982). The 3 forms have 0, 1+, and 2+ charges to account forelectrophoretic differences (Margolis, 1982). (The nomenclature of theapolipoprotein E isoforms, defined by isoelectric focusing, has gonethrough an evolution.) E3 is the most frequent (‘wildtype’) isoform. Asreviewed by Smit et al. (J. Lipid Res. 31: 45-53, 1990), E4 differs fromE3 by a cys-to-arg change at position 112 and is designatedE4(cys112-to-arg). Four different mutations giving a band at the E2position with isoelectric focusing have been described:E2(arg158-to-cys), E2(lys146-to-gln), E2(arg145-to-cys) andE2-Christchurch(arg136-to-ser). E2(arg158-to-cys) is the most common ofthe 4.

[0402] In a comprehensive review of apoE variants, de Knijffet al.(Clin. Invest. 88: 643-655, 1994) found that 30 variants had beencharacterized, including the most common variant, apoE3. To that time,14 apoE variants had been found to be associated with familialdysbetalipoproteinemia, characterized by elevated plasma cholesterol andtriglyceride levels and an increased risk for atherosclerosis.

[0403] Data on gene frequencies of apoE allelic variants were tabulatedby Roychoudhury and Nei (New York: Oxford Univ. Press (pub.) 1988).Gerdes et al. (Genet. Epidemiol. 9:155-167, 1992) and Gerdes et al.(Hum. Genet. 98: 546-550, 1996) reported the frequency of apoEpolymorphisms in the Danish population and in Greenland Inuit,respectively, in relation to the findings in 45 other study populationsaround the world.

[0404] In normal individuals, chylomicron remnants and very low densitylipoprotein (VLDL) remnants are rapidly removed from the circulation byreceptor-mediated endocytosis in the liver. In familialdysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III),increased plasma cholesterol and triglycerides are the consequence ofimpaired clearance of chylomicron and VLDL remnants because of a defectin apolipoprotein E. Accumulation of the remnants can result inxanthomatosis and premature coronary and/or peripheral vascular disease.Hyperlipoproteinemia III can be either due to primary heritable defectsin apolipoprotein metabolism or secondary to other conditions such ashypothyroidism, systemic lupus erythematosus, or diabetic acidosis. Mostpatients with familialdysbetalipoproteinemia (HLP III) are homozygousfor the E2 isoform (J. Lipid Res. 23: 1224-1235, Breslow et al., 1982).Only rarely does the disorder occur with the heterozygous phenotypesE3E2 or E4E2. The E2 isoform shows defective binding of remnants tohepatic lipoprotein receptors (Schneider et al., J. Clin. Invest. 68:1075-1085, 1981; Rall et al., Proc. Nat. Acad. Sci. 79: 4696-4700, 1982)and delayed clearance from plasma (Gregg et al., Science 211: 584-586,1981). Additional genetic and/or environmental factors must be requiredfor development of the disorder, however, because only 1-4% of E2E2homozygotes develop familial dysbetalipoproteinemia. Since the defect inthis disorder involves the exogenous cholesterol transport system, thedegree of hypercholesterolemia is sensitive to the level of cholesterolin the diet (Brown et al., Science 212: 628-635, 1981). Even on a normaldiet, the patient may show increased plasma cholesterol and the presenceof an abnormal lipoprotein called beta-VLDL. VLDL in general is markedlyincreased while LDL is reduced.

[0405] Carbohydrate induces or exacerbates the hyperlipidemia, resultingin marked variability in plasma levels and ready therapy through dietarymeans. Often tuberous and planar and sometimes tendon xanthomas occur aswell as precocious atherosclerosis and abnormal glucose tolerance.Tuberous and tuberoeruptivexanthomas are particularly characteristic.Hazzard (1978) demonstrated the eliciting effects of electric shock in aman revived from accidental electrocution and later showing strikingxanthomas of the palms. Development of the phenotype is age dependent,being rarely evident before the third decade. The nosography of the typeIII hyperlipoproteinemia phenotype up to 1977 was reviewed by Levy andMorganroth (Ann. Intern. Med. 87: 625-628, 1977). Subsequent descriptionof specific biochemical alterations in apolipoprotein structure andmetabolism has proven this phenotype to be genetically heterogeneous. Inthe first application of apoprotein immunoassay to this group ofdisorders, Kushwaha et al. (Ann. Intern. Med. 87: 517-525, 1977) foundthat apolipoprotein E (arginine-rich lipoprotein) is high in the VLDlipoproteins of type III. They also found that exogenous estrogen, whichstimulates triglyceride production in normal women and those withendogenous hypertriglyceridemia, exerted a paradoxicalhypotriglyceridemic effect in this disorder (Kushwaha et al., 1977). Theabnormal pattern of apoE by isoelectric focusing (IEF), specifically,the absence of apoE3, is the most characteristic biochemical feature ofHLP III. Gregg et al. (1981) showed that apoE isolated from subjectswith type III HLP had a decreased fractional catabolic rate in vivo inboth type III HLP patients and normal persons.

[0406] Hazzard et al. (Metabolism 30: 79-88, 1981) reported on the largeO'Donnell kindred, studied because of a proband with type III HLP. Theystudied specifically the VLDL isoapolipoprotein E distributions. Thefindings confirmed earlier work indicating that the ratio of E3 to E2 isdetermined by two apoE3 alleles, designated d and n, which produce threephenotypes, apoE3-d, apoE3-nd, and apoE3-n, corresponding to the low,intermediate, and high ratios. Ghiselli et al. (Science 214: 1239-1241,1981) studied a black kindred with type III HLP due to deficiency ofapolipoprotein E. No plasma apolipoprotein E could be detected. Otherfamilies with type III HLP have had increased amounts of an abnormalapoE. In addition, the patients of Ghiselli et al. (1981) had only mildhypertriglyceridemia, increased LDL cholesterol, and a much higher ratioof VLDL cholesterol to plasma triglyceride than reported in other typeIII HLP families. The proband was a 60-year-old woman with a 10-yearhistory of tuberoeruptive xanthomas of the elbows and knees, a 3-yearhistory of angina pectoris, and 80% narrowing of the first diagonalcoronary artery by arteriography. Her father had xanthomas and died atage 62 of myocardial infarction. Her mother was alive and well at age86. Three of 7 sibs also had xanthomas; her 2 offspring had noxanthomas. The evidence suggests that apoE is important for thecatabolism of chylomicron fragments. The affected persons in the familystudied by Ghiselli et al. (1981) had plasma levels of apoE less than0.05 mg/dl by radioimmunoassay, and no structural variants of apoE weredetected by immunoblot of plasma or VLDL separated by 2-dimensional gelelectrophoresis. Anchors et al. (Biochem. Biophys. Res. Commun. 134:937-943, 1986) reported that the apoE gene was present in theapoE-deficient patient and that there were no major insertions ordeletions in the gene by Southern blot analysis. Bloodmonocyte-macrophages isolated from a patient contained levels of apoEmRNA 1 to 3% of that present in monocyte-macrophages isolated fromnormal subjects. The mRNA from the patient appeared to be of normalsize. Anchors et al. (1986) suggested that the decreased apoE mRNA mightbe due to a defect in transcription or processing of the primarytranscript or to instability of the apoE mRNA. The decreased plasmalevel of apoE resulted in delayed clearance of remnants oftriglyceride-rich lipoproteins, hyperlipidemia, and the phenotype oftype III HLP. In the kindred with apolipoprotein E deficiency studied byGhiselli et al. (1981), the defect was shown by Cladaras et al. (J.Biol. Chem. 262: 2310-2315, 1987) to involve an acceptor splice sitemutation in intron 3 of the APOE gene (107741.0005). ApoE, a mainapoprotein of the chylomicron, binds to a specific receptor on livercells and peripheral cells. The E2 variant binds less readily. A defectin the receptor for apoE on liver and peripheral cells might also leadto dysbetalipoproteinemia, but such has not been observed. Weisgraber etal. (Biol. Chem. 257: 2518-2521, 1982) showed that human E apoprotein ofthe E2 form, which contains cysteine (rather than arginine) at both ofthe 2 variable sites, binds poorly with cell surface receptors, whereasE3 and E4 bind well. They postulated that a positively charged residueat variable site B is important for normal binding. To test thehypothesis, they treated E2 apoE with cysteamine to convert cysteine toa positively charged lysine analog. This resulted in a marked increasein the binding activity of the E2 apoE. Although nearly every type IIIhyperlipoproteinemic person has the E2/E2 phenotype, 95 to 99% ofpersons with this phenotype do not have type III HLP nor do they haveelevated plasma cholesterol levels. Rall et al. (J. Clin. Invest. 72:1288-1297, 1983) showed that apoE2 of hypo-, normo-, andhypercholesterolemic subjects showed the same severe functionalabnormalities. Thus, factors in addition to the defective receptorbinding activity of the apoE2 are necessary for manifestation of typeIII HLP. A variety of factors exacerbate or modulate type III. In women,it most often occurs after the menopause and in such patients isparticularly sensitive to estrogen therapy. Hypothyroidism exacerbatestype III and thyroid hormone is known to enhance receptor-mediatedlipoprotein metabolism. Obesity, diabetes and age are associated withincreased hepatic synthesis of VLDL and/or cholesterol; occurrence oftype III in E2/E2 persons with these factors may be explained thereby.Furthermore, the defect in familial combined HLP (144250), which is, itseems, combined with E2/E2 in the production of type III (Utermann etal., 1979; Hazzard et al., 1981), may be hepatic overproduction ofcholesterol and VLDL. As pointed out by Brown and Goldstein (J. Clin.Invest. 72: 743-747, 1983), familial hypercholesterolemia (FH) is agenetic defect of the LDL receptor (LDLR; 143890), whereas familialdysbetalipoproteinemia is a genetic defect in a ligand. The puzzle thatall apoE2/2 homozygotes do not have extremely high plasma levels of IDLand chylomicron remnants (apoE-containing lipoproteins) may be solved bythe observation that the lipoprotein levels in these patients areexquisitely sensitive to factors that reduce hepatic LDL receptors,e.g., age, decreased levels of thyroid hormone and estrogen, and thegenetic defect of FH. Presumably, high levels of hepatic LDL receptorscan compensate for the genetic binding defect of E2 homozygotes. Gregget al. (Lancet I: 353, 1983) suggested that apoE4 is associated withsevere type V hyperlipoproteinemia in a manner comparable to theassociation of apoE2 with type III. Vogel et al. (Proc. Nat. Acad. Sci.82: 8696-8700, 1985) showed that large amounts of apoE can be producedby E. coli transformed with a plasmid containing a human apoE cDNA. Theuse in studies of structure-function relationships through production ofsite-specific mutants was noted. Wardell et al. (J. Biol. Chem. 264:21205-21210, 1989) demonstrated that the defect is a 7-amino acidinsertion that represents a tandem repeat of amino acid residues 121-127resulting in the normal protein having 306 amino acids rather than thenormal 299. Schaefer et al. (J. Clin. Invest. 78: 1206-1219, 1986)described a unique American black kindred with premature cardiovasculardisease, tuberoeruptive xanthomas, and type III HLP associated withfamilial apolipoprotein E deficiency. Four homozygotes had markedincreases in cholesterol-rich, very low density lipoproteins andintermediate density lipoproteins (IDL). Homozygotes had only traceamounts of plasma apoE, and accumulations of apoB-48 (107730) and apoA-4(107690) in VLDL, IDL, and low density lipoproteins. Obligateheterozygotes generally had normal plasma lipids and mean plasma apoEconcentrations that were 42% of normal. The findings indicated that apoEis essential for the normal catabolism of triglyceride-rich lipoproteinconstituents. It had been shown that cultured peripheral blood monocytessynthesized low amounts of 2 aberrant forms of apoE mRNA but produced noimmunoprecipitable forms of apoE. The expression studies were donecomparing the normal and abnormal APOE genes transfected into mousecells in combination with the mouse metallothionein I promoter. Bersotet al. (J. Clin. Invest. 72: 1024-1033, 1983) studied a typicaldysbetalipoproteinemia characterized by severe hypercholesterolemia andhypertriglyceridemia, xanthomatosis, premature vascular disease, theapoE3/3 phenotype (rather than the classic E2/2 phenotype), and apreponderance of beta-VLDL. They showed that the beta-VLDL from thesesubjects stimulated cholesteryl ester accumulation in mouse peritonealmacrophages. They suggested that the accelerated vascular diseaseresults from this uptake by macrophages which are converted into thefoam cells of atherosclerotic lesions. Smit et al. (Clin. Genet. 32:335-341, 1987) described 3 out of 41 Dutch dysbetalipoproteinemicpatients who were apparent E3/E2 heterozygotes rather than the usualE2/E2 homozygotes. All 3 genetically unrelated patients showed anuncommon E2 allele that contained only 1 cysteine residue. The uncommonallele cosegregated with familial dysbetalipoproteinemia which in thesefamilies seemed to behave as a dominant. Smit et al. (1990) showed thatthese 3 unrelated patients had E2(lys146-to-gln). Eto et al. (Clin.Genet. 36: 183-188, 1989) presented data from Japan indicating that boththe E2 allele and the E4 allele are associated with an increased risk ofischemic heart disease as compared with the E3 allele. Boerwinkle andUtermann (Am. J. Hum. Genet. 42: 104-112, 1988) studied the simultaneouseffect of apolipoprotein E polymorphism on apolipoprotein E,apolipoprotein B, and cholesterol metabolism. Since both apoB and apoEbind to the LDL receptor and since the different isoforms show differentbinding affinity, these effects are not unexpected. Subjects withtypical dysbetalipoproteinemia are homozygous for an amino acidsubstitution in apoE at residue 158 (107741.0001). Chappell (. Clin.Invest. 84: 1906-1915, 1989) studied the binding properties oflipoproteins in 9 subjects with dysbetalipoproteinemia who were eitherhomozygous or heterozygous for substitutions at a typical sites: atresidue 142 in 6, at 145 in 2, and at 146 in 1. In 5 of 19 Australianmen, aged 30 to 50, who were referred for coronary angioplasty (26%),van Bockxmeer and Mamotte (Lancet 340: 879-880, 1992) observedhomozygosity for E4. This represented a 16-fold increase compared withcontrols. Payne et al. (Lancet 340: 1350, 1992), O'Malley andIllingworth (Lancet 340: 1350-1351, 1992), and de Knijffet al. (Lancet340: 1350-1351, 1992) expressed doubts concerning a relationship betweenE4 and atherosclerosis. Feussner et al. (Am. J. Med. Genet. 65: 149-154,1996) reported a 20-year-old man with a combination of type IIIhyperlipoproteinemia and heterozygous familial hypercholesterolemia (FH;143890). Multiple xanthomas were evident on the elbows, interphalangealjoints and interdigital webs of the hands. Lipid-lowering therapy causedsignificant decrease of cholesterol and triglycerides as well asregression of the xanthomas. Flat xanthomas of the interdigital webswere also described in 3 out of 4 previously reported patients withcombination of these disorders of lipoprotein metabolism. Feussner etal. (1996) stated that these xanthomas may indicate compoundheterozygosity (actually double heterozygosity) for type IIIhyperlipoproteinemia and FH.

[0407] Saunders et al. (Neurology 43: 1467-1472, 1993) reported anincreased frequency of the E4 allele in a small prospective series ofpossible-probable AD patients presenting to the memory disorders clinicat Duke University, in comparison with spouse controls. Corder et al.(Science 261: 921-923, 1993) found that the APOE*E4 allele is associatedwith the late-onset familial and sporadic forms of Alzheimer disease. In42 families with the late-onset form of Alzheimer disease (AD2; 104310),the gene had been mapped to the same region of chromosome 19 as the APOEgene. Corder et al. (1993) found that the risk for AD increased from 20to 90% and mean age of onset decreased from 84 to 68 years withincreasing number of APOE*E4 alleles. Homozygosity for APOE*E4 wasvirtually sufficient to cause AD by age 80. Lannfelt et al. (AlzheimerDis. Assoc. Disord. 9: 166-169, 1995) compared allelic frequency ofapolipoprotein E4 in 13 dizygotic twin pairs discordant for Alzheimerdisease and found the expected increased frequency of the epsilon-4allele in Alzheimer compared to healthy cotwins. In a well-knownAmerican kindred with late-onset Alzheimer disease, descended from acouple who immigrated to the United States from France in the 18thcentury, Borgaonkar et al. (Lancet 342: 625, 1993) found evidenceconfirming a dosage effect of the E4 allele of 6 affected individuals; 4E4/E4 homozygotes had onset in their 60s, whereas 2 E4/E3 heterozygoteshad onset at ages 77 and 78, respectively. Apolipoprotein E is found insenile plaques, congophilic angiopathy, and neurofibrillary tangles ofAlzheimer disease. Strittmatter et al. (Proc. Nat. Acad. Sci. 90:1977-1981, 1993) compared the binding of synthetic amyloid beta peptideto purified APOE4 and APOE3, the most common isoforms. Both isoforms inoxidized form bound the amyloid beta peptide; however, binding to APOE4was observed in minutes, whereas binding to APOE3 required hours.Strittmatter et al. (1993) concluded that binding of amyloid betapeptide by oxidized apoE may determine their sequestration and thatisoform-specific differences in apoE binding or oxidation may beinvolved in the pathogenesis of the lesions of Alzheimer disease. In astudy of 91 patients with sporadic Alzheimer disease and 74 controls,Poirier et al. (Lancet 342: 697-699, 1993) found a significantassociation between E4 and sporadic AD. The association was morepronounced in women. Scott (1993) pointed to the need for caution in theapplication of knowledge gained through screening of E4 in relation tothis very common disorder. In a case-control study of 338 centenarianscompared with adults aged 20 to 70 years of age, Schachter et al.(Lancet 342: 696, 1994) found that the E4 allele of apoE, which promotespremature atherosclerosis, was significantly less frequent incentenarians than in controls (p=less than 0.001), while the frequencyof the E2 allele, associated previously with types III and IVhyperlipidemia, was significantly increased (p=less than 0.01). Talbotet al. (Lancet 343: 1432-1433, 1994) presented data suggesting that theE2 allele may confer protection against Alzheimer disease and that itseffect is not simply the absence of an E4 allele. Corder et al. (NatureGenet. 7: 180-184, 1994) presented data demonstrating a protectiveeffect of the E2 allele, in addition to the dosage effect of the E4allele in sporadic AD. Although a substantial proportion (65%) of AD isattributable to the presence of E4 alleles, risk of AD is lowest insubjects with the E2/E3 genotype, with an additional 23% of ADattributable to the absence of an E2 allele. The opposite actions of theE2 and E4 alleles were interpreted by Corder et al. (1994) to providefurther support for the direct involvement of APOE in the pathogenesisof AD. Sanan et al. (J. Clin. Invest. 94: 860-869, 1994) demonstratedthat the E4 isoform binds to the beta amyloid (A-beta) peptide morerapidly than the E3 isoform. Soluble SDS-stable complexes of E3 or E4,formed by coincubation with the A-beta peptide, precipitated afterseveral days of incubation at 37 degrees C., with E4 complexesprecipitating more rapidly than E3 complexes.

[0408] Hyman et al. (Arch. Neurol. 53: 215, 1996) demonstratedhomozygosity for the E4 genotype in an 86-year-old man with no historyof neurologic disease and whose autopsy did not reveal anyneurofibrillary tangles and only rare mature senile plaques. Thissuggested to the authors that inheritance of apoE4 does not necessarilyresult in the development of dementia or Alzheimer disease. Myers et al.(Neurology 46: 673-677, 1996) examined the association of apolipoproteinE4 with Alzheimer disease and other dementias in 1,030 elderlyindividuals in the Framingham Study cohort. They found an increased riskfor Alzheimer disease as well as other dementias in patients who werehomozygous or heterozygous for E4. However they pointed out that mostapoE4 carriers do not develop dementia and about one-half of Alzheimerdisease is not associated with apoE4. Kawamata et al. (J. Neurol.Neurosurg. Psychiat. 57: 1414-1416, 1994) examined the E4 frequency in40 patients with late-onset sporadic Alzheimer disease, 13 patients withearly-onset sporadic Alzheimer disease, 19 patients with vasculardementia, and 49 nondemented control subjects. In the late-onsetsporadic Alzheimer group, the allele frequency was 0.25, considerablyhigher than the frequency in controls, 0.09. In contrast, there was noincreased frequency in early-onset sporadic Alzheimer disease or inpatients with vascular dementia. Olichney et al. (Neurology 47: 190-196,1996) found that the apolipoprotein E4 allele is strongly associatedwith increased neuritic plaques but not neocortical or fibrillarytangles in both Alzheimer disease and the Lewy body variant. Greenberget al. (Ann. Neurol. 38: 254-259, 1995) found that the presence ofapolipoprotein E4 increased the odds ratio for moderate or severecerebral amyloid angiopathy significantly, even after controlling forthe presence of Alzheimer disease. In a postmortem study, Greenberg etal. (Neurology 50: 961-965, 1998) found an association betweenapolipoprotein E2 and vasculopathy in cerebral amyloid angiopathy. Of 75brains with complete amyloid replacement of vessel walls, only 23 hadaccompanying signs of hemorrhage in cracks of the vessel wall. Thefrequency of apolipoprotein E2 was significantly higher in the groupwith vasculopathy. The authors suggested that apolipoprotein E2 and E4might promote hemorrhage through separate mechanisms: E4 by enhancingamyloid deposition and E2 by promoting rupture. O'Donnell et al. (NewEng. J. Med. 342: 240-245, 2000) identified a specific apolipoprotein Egenotype as a risk factor for early recurrence of cerebral amyloidangiopathy: carriers of the E2 (107741.0001) or E4 (107741.0016) allelehad an increased risk for early recurrence compared to individuals withthe E3/E3 (107741.0015) genotype. Kawamata et al. (1994) speculated thatthe lower magnitude of the raised frequency of E4 in the Japanese groupcompared to that of North American families may be due to a lower E4frequency in the normal Japanese population and lower morbidity fromAlzheimer disease in Japan. Nalbantoglu et al. (Ann. Neurol. 36:889-895, 1994) performed apolipoprotein analysis on 113 postmortem casesof sporadic Alzheimer disease and 77 control brains in Montreal. In thispopulation, the odds ratio associating E4 with Alzheimer disease was15.5 and the population attributable risk was 0.53. Yoshizawa et al.(Ann. Neurol. 36: 656-659, 1994) examined the apolipoprotein genotypesin 83 Japanese patients with Alzheimer disease. They found a significantincrease in apoE4 frequency in late-onset sporadic Alzheimer disease anda mild increase of apoE4 frequency in late- and early-onset familialAlzheimer disease. In contrast, they found no association between apoE4and early-onset sporadic Alzheimer disease. Lucotte et al. (Ann. Neurol.36: 681-682, 1994) examined the apoE4 frequency in 132 French patientswith onset of Alzheimer disease after 60 years of age. They found thathomozygosity for the E4 allele was associated with a younger age ofdisease occurrence than was heterozygosity or absence of the E4 allele.Osuntokun et al. (Ann. Neurol. 38: 463-465, 1995) found no associationbetween E4 and Alzheimer disease in elderly Nigerians, in contrast tothe strong association reported in their previous study of AfricanAmericans in Indianapolis. Levy-Lahad et al. (Ann. Neurol. 38: 678-680,1995) found that the epsilon 4 allele did not affect the age of onset ineither Alzheimer disease type 4 present in Volga Germans (600753) orAlzheimer disease type 3 (104311). This suggested to them that someforms of early onset familial Alzheimer disease are not influenced bythe apolipoprotein E system. Bennett et al. (Am. J. Med. Genet. 60:1-6,1995) examined the APOE genotype in family history-positive andfamily history-negative cases of Alzheimer disease and found adistortion of the APOE allele frequencies similar to those with previousstudies. However, they also examined the allele distribution of at-risksibs and found an excess of the E4 allele which did not differ from thatof affected sibs. In these families, they found no evidence for linkagebetween the APOE4 locus and Alzheimer disease. They concluded that theAPOE locus is neither necessary nor sufficient to cause Alzheimerdisease and speculated that it may modify the preclinical progression,and therefore the age of onset, in people otherwise predisposed todevelop Alzheimer disease. Head injury is an epidemiologic risk factorfor Alzheimer disease and deposition of A-beta occurs in approximatelyone-third of individuals dying after severe headinjury. Nicoll et al.(Nature Med. 1: 135-137, 1995) found that the frequency of APOE4 inindividuals with A-beta deposition following head injury (0.52) washigher than in most studies of Alzheimer disease, while in thosehead-injured individuals without A-beta deposition, the APOE4 frequency(0.16) was similar to controls without Alzheimer disease (P=less than0.00001). Thus, environmental and genetic risk factors for Alzheimerdisease may act additively. In a prospective study of 69 patients withsevere blunt trauma to the head, Friedman et al. (Neurology 52: 244-248,1999) found an odds ratio of 5.69 for more than 7 days ofunconsciousness and 13.93 for a suboptimal neurologic outcome at 6months for individuals with an APOE4 allele compared to those withoutthat allele. In a review of apolipoprotein E and Alzheimer disease,Strittmatter and Roses (Proc. Nat. Acad. Sci. 90: 1977-1981, 1995)pointed out that isoform-specific differences have been identified inthe binding of apoE to the microtubule-associated protein tau (157140),which forms the paired helical filament and neurofibrillary tangles, andto amyloid beta peptide (104760), a major component of the neuriticplaque. Identification of apoE in the cytoplasm of human neurons andisoform-specific binding of apoE to the microtubule-associated proteintau and MAP-2 (157130) make it possible that apoE may affect microtubulefunction in the Alzheimer brain. Blennow et al. (Neuroreport 5:2534-2536, 1994) demonstrated a significant reduction of CSFapolipoprotein E in Alzheimer disease compared to that of controls. Theysuggested that the increased reutilization of apolipoprotein E lipidcomplexes in the brain in Alzheimer disease may explain the low CSFconcentration.

[0409] The observation that the APOE4 allele is neither necessary norsufficient for the expression of AD emphasizes the significance of otherenvironmental or genetic factors that, either in conjunction with APOE4or alone, increase the risk of AD. Kamboh et al. (Nature Genet. 10:486-488, 1995) noted that among the candidate genes that might affectthe risk for Alzheimer disease is alpha-1-antichymotrypsin (AACT;107280) because, like APOE protein, AACT binds to beta-amyloid peptidewith high affinity in the filamentous deposits found in the AD brain.Additionally, it serves as a strong stimulatory factor in thepolymerization of beta-amyloid peptide into amyloid filaments. Kamboh etal. (Am. J. Hum. Genet. 58: 574-584, 1995) demonstrated that a commonpolymorphism in the signal peptide of AACT (107280.0005) confers asignificant risk for AD and that the APOE4 gene dosage effect associatedwith AD risk is significantly modified by the AACT polymorphism. Theyidentified the combination of the AACT ‘AA’ genotype with the APOE4/4genotype as a potential susceptibility marker for AD, as its frequencywas {fraction (1/17)} in the AD group compared to {fraction (1/313)} inthe general population controls. It is noteworthy that one form ofAlzheimer disease (designated Alzheimer type 3, 104311), like AACT, mapsto 14q; however, AACT and AD3 are located at somewhat different sites on14q. Tang et al. (1996) compared relative risks by APOE genotypes in acollection of cases and controls from 3 ethnic groups in a New Yorkcommunity. The relative risk for Alzheimer disease associated with APOE4homozygosity was increased in all ethnic groups: African AmericanRR=3.0; Caucasian RR=7.3; and Hispanic RR=2.5 (compared with the RR withAPOE3 homozygosity). The risk was also increased for APOE4 heterozygousCaucasians and Hispanics, but not for African Americans. The agedistribution of the proportion of Caucasian and Hispanics without AD wasconsistently lower for APOE4 homozygous and APOE4 heterozygousindividuals than for those with other APOE genotypes. In AfricanAmericans this relationship was observed only in APOE4 homozygotes.Differences in risk among APOE4 heterozygous African Americans suggestedto the authors that other genetic or environmental factors may modifythe effect of APOE4 in some populations. In a study of 85 Scottishpersons with early onset Alzheimer disease, St Clair et al. (J. Med.Genet. 32: 642-644, 1995) found highly significant enrichment for bothhomozygous and heterozygous APOE epsilon-4 allele carriers in bothfamilial and sporadic cases with a pattern closely resembling that inlate onset AD. As reviewed earlier, the APOE4 allele is associated withsporadic and late-onset familial Alzheimer disease. Gene dose has aneffect on risk of developing AD, age of onset, accumulation of senileplaques in the brain, and reduction of choline acetyltransferase(118490) in the hippocampus of AD patients. Poirier et al. (Proc. Nat.Acad. Sci. 92: 12260-12264, 1995) examined the effect of APOE4 allelecopy number on pre- and postsynaptic markers of cholinergic activity.APOE4 allele copy number showed an inverse relationship with residualbrain CHAT activity and nicotinic receptor binding sites in both thehippocampal formation and the temporal cortex of AD subjects. ADsubjects lacking the APOE4 allele showed CHAT activities close to orwithin the age-matched normal control range. Poirier et al. (1995) thenassessed the effect of the APOE4 allele on cholinomimetic drugresponsiveness in 40 AD patients who completed a double-blind, 30-weekclinical trial of the cholinesterase inhibitor tacrine. Results showedthat more than 80% of APOE4-negative AD patients showed markedimprovement after 30 weeks, whereas 60% of APOE4 carriers had poorresponses. Polyikoski et al. (New Eng. J. Med. 333: 1242-1247, 1995)reported on an autopsy study involving neuropathologic analysis and DNAanalysis of frozen blood specimens performed in 92 of 271 persons whowere at least 85 years of age, who had been living in Vantaa, Finland,on Apr. 1, 1991, and who had died between that time and the end of 1993.All subjects had been tested for dementia. Apolipoprotein E genotypingwas done with a solid-phase minisequencing technique. The percentage ofcortex occupied by methenamine silver-stained plaques was used as anestimate of the extent of beta-amyloid protein deposition. They foundthat the APOE4 allele was significantly associated with Alzheimerdisease. Even in elderly subjects without dementia, the apolipoproteinE4 genotype was related to the degree of deposition of beta-amyloidprotein in the cerebral cortex. Reiman et al. (New Eng. J. Med. 334:752-758, 1996) found that in late middle age, cognitively normalsubjects who were homozygous for the APOE4 allele had reduced glucosemetabolism in the same regions of the brain as in patients with probableAlzheimer disease. These findings provided preclinical evidence that thepresence of the APOE4 allele is a risk factor for Alzheimer disease.Positron-emission tomography (PET) was used in these studies; Reiman etal. (1996) suggested that PET may offer a relatively rapid way oftesting treatments to prevent Alzheimer disease in the future. Inlate-onset familial AD, women have a significantly higher risk ofdeveloping the disease than do men. Studying 58 late-onset familial ADkindreds, Payami et al. (Am. J. Hum. Genet. 58: 803-811, 1996) detecteda significant gender difference for the APOE4 heterozygous genotype. Inwomen, APOE4 heterozygotes had higher risk than those without APOE4;there was no significant difference between APOE4 heterozygotes andAPOE4 homozygotes. In men, APOE4 heterozygotes had lower risk than APOE4homozygotes; there was no significant difference between APOE4heterozygotes and those without APOE4. A direct comparison of APOE4heterozygous men and women revealed a significant 2-fold increased riskin women. These results were corroborated in studies of 15autopsy-confirmed AD kindreds from the National Cell Repository atIndiana University Alzheimer Disease Center. Mahley (Science 240:622-630, 1988) provided a review documenting the expanding role of apoEas a cholesterol transport protein in cell biology. The pronouncedproduction and accumulation of apoE in response to peripheral nerveinjury and during the regenerative process indicates, for example, thatapoE plays a prominent role in the redistribution of cholesterol to theneurites for membrane biosynthesis during axon elongation and to theSchwann cells for myelin formation. Poirier (Trends Neurol. Sci. 17:525-530, 1994) reviewed the coordinated expression of apoE and itsreceptor, the apoE/apoB LDL receptor (143890), in the regulation oftransport of cholesterol and phospholipids during the early andintermediate phases of reinnervation, both in the peripheral and in thecentral nervous system. He proposed that the linkage of the E4 allele toAlzheimer disease (104300) may represent dysfunction of the lipidtransport system associated with compensatory sprouting and synapticremodeling central to the Alzheimer disease process. Tomimoto et al.(Acta Neuropath. 90: 608-614, 1995) found only 3 cases with focalaccumulation of apolipoprotein E in dystrophic axons and accompanyingmacrophages in 9 cases of cerebral vascular disease and 4 controlsubjects. The results suggested to the authors that apolipoprotein E mayhave a role in recycling cholesterol in other membrane components in thebrain, but that this phenomenon is restricted to the periphery ofinfarctions and may be less prominent than in the peripheral nervoussystem. Egensperger et al. (Biochem. Biophys. Res. Commun. 224: 484-486,1996) determined the apoE allele frequencies in 35 subjects withneuropathologically confirmed Lewy body parkinsonism with and withoutconcomitant Alzheimer lesions, 27 patients with AD, and 54 controls.They concluded that the apoE4 allele does not function as a risk factorwhich influences the development of AD lesions in PD. In aggregate, theassociation studies on apoE in Alzheimer disease suggest epsilon-4accelerates the neurodegenerative process in Alzheimer disease. However,in 3 independent studies, Kurz et al. (Neurology 47: 440-443, 1996),Growdon et al. (Neurology 47: 444-448, 1996), and Asada et al.(Neurology 47: 603 only 1996) found no differences in the clinical rateof decline of newly diagnosed Alzheimer disease patients with or withoutthe epsilon-4 allele. Bickeboller et al. (Am. J. Hum. Genet. 60:439-446, 1997) confirmed the increased risk for AD associated with theAPOE4 allele in 417 patients compared with 1,030 control subjects. Whencompared to the APOE3 allele, the authors demonstrated an increased riskassociated with the APOE4 allele (odds ratio=2.7) and a protectiveeffect of the APOE2 allele (odds ratio=0.5). An effect of E4 alleledosage on susceptibility was confirmed: the odds ratio of E4/E4 versusE3/E3=11.2; odds ratio of E3/E4 versus E3/E3=2.2. In E3/E4 individuals,sex-specific lifetime risk estimates by age 85 years (i.e., sex-specificpenetrances by age 85 years) were 0.14 for men and 0.17 for women.Houlden et al. (Am. J. Med. Genet. 81: 117-121, 1998) found that theAPOE genotype is only a risk factor for early-onset AD families with nolesion detectable in the presenilin or APP gene. Meyer et al. (NatureGenet. 19: 321-322, 1998) presented data on an elderly population whichsuggested that apoE genotype influences the age-specific risk ofAlzheimer disease but that, regardless of apoE genotype, more than halfof the population will not develop AD by age 100. ApoE genotype did notappear to influence whether subjects will develop AD, but the study didconfirm that the apoE4 alleles influence when susceptible individualswill develop AD. The findings could be explained by a gene or genesindependent of apoE that condition vulnerability. Wiebusch et al. (Hum.Genet. 104: 158-163, 1999) conducted a case-control study of 135pathologically confirmed AD cases and 70 non-AD controls (age of deathgreater than or equal to 60 years) in whom they genotyped for APOEepsilon-4 and BCHE-K (177400.0005). The allelic frequency of BCHE-K was0.13 in controls and 0.23 in cases, giving a carrier odds ratio of 2.1(95% confidence interval (CI) 1.1-4.1) for BCHE-K in confirmed AD. In anolder subsample of 27 controls and 89 AD cases with ages of deathgreater than or equal to 75 years, the carrier odds ratio increased to4.5 (95% CI 1.4-15) for BCHE-K. The BCHE-K association with AD becameeven more prominent in carriers of APOE epsilon-4. Only 3 of 19 controlscompared with 39 of 81 cases carried both, giving an odds ratio of 5.0(95% CI 1.3-19) for BCHE-K carriers within APOE epsilon-4 carriers. Theauthors concluded that the BCHE-K polymorphism is a susceptibilityfactor for AD and enhances the AD risk from APOE epsilon-4 in anage-dependent manner.

[0410] Saunders et al. (Lancet 342: 710-711, 1993) found no associationof E4 with other amyloid-forming diseases, i.e., Creutzfeldt-Jakobdisease (CJD; 123400), familial amyloidotic polyneuropathy, and Downsyndrome (190685). On the other hand, Amouyel et al. (Lancet 344:1315-1318, 1994) concluded that E4 is a major susceptibility factor forCJD. They found a relative risk of CJD between subjects with at leastone E4 allele and subjects with none to range between 1.8 and 4.2,depending on the control group used. A variation in disease duration wasalso noted, depending on apoE genotype, with an increase in duration ofillness in E2 allele carriers. Frisoni et al. (Stroke 25: 1703, 1994)assessed the apoE allele frequency in 51 elderly control subjects, 23subjects with vascular dementia, and 93 patients with Alzheimer disease.There was increased frequency of the E4 allele both in Alzheimer diseaseand in vascular dementia with respect to both elderly and young controlsubjects. There was no difference in the proportion of E2, E3, and E4frequency in Alzheimer disease and vascular dementia patients. Slooteret al. (Lancet 348: 334 only, 1996) compared E4 allele frequency between185 patients with Alzheimer disease and those with other types ofdementia. The authors found little predictive value in distinguishingAlzheimer patients from those with other forms of dementia using APOEgenotyping. In contrast, Mahieux et al. (Stroke 25: 1703-1704, 1994)found an increase of E4 in Alzheimer disease, but not in vasculardementia. They speculated that the difference between their results andthose of Frisoni et al. (1994) may be attributable to the small size ofthe groups or to the different mean ages of the populations that theystudied. McCarron et al. (Neurology 53: 1308-1311, 1999) performed ametaanalysis that demonstrated a significantly higher frequency of E4carriers in individuals with ischemic cerebrovascular disease than incontrol subjects (odds ratio, 1.73). Myers et al. (1996) examined theassociation of apolipoprotein E4 with Alzheimer disease and otherdementias in 1,030 elderly individuals in the Framingham Study cohort.They found an increased risk for Alzheimer disease as well as otherdementias in patients who were homozygous or heterozygous for E4.However they pointed out that most apoE4 carriers do not developdementia and about one-half of Alzheimer disease is not associated withapoE4. Blesa et al. (Ann. Neurol. 39: 548-551, 1996) found an apoEepsilon-4 frequency of 0.315 in patients with age-related memory declinewithout dementia, similar to the 0.293 allele frequency found in anAlzheimer disease group. This contrasted to the frequency of 0.057 foundin their control group. Payami et al. (Am. J. Hum. Genet. 60: 948-956,1997) reported the results of a prospective case-control study thatenlisted 114 Caucasian subjects who were physically healthy andcognitively intact at age 75 years and who were followed, for an averageof 4 years, with neurologic, psychometric, and neuroimagingexaminations. Excellent health at entry did not protect againstcognitive decline. Incidence of cognitive decline rose sharply with age.E4 and a family history of dementia (independent of E4) were associatedwith an earlier age at onset of dementia. Subjects who had E4 or afamily history of dementia had a 9-fold-higher age-specific risk fordementia than did those who had neither. From these observations, Payamiet al. (1997) suggested that the rate of cognitive decline increaseswith age and that APOE and other familial/genetic factors influence theonset age throughout life. In a study of 79 patients with Parkinsondisease, 22 of whom were demented, Marder et al. (Neurology 44:1330-1331, 1994) found that the E4 allele frequency was 0.13 in patientswithout dementia and 0.068 in those with dementia as opposed to acontrol value of 0.102. The authors concluded that the biologic basisfor dementia in Parkinson disease differs from that of Alzheimerdisease. Tabaton et al. (Neurology 45: 1764-1765, 1995) found that,although apolipoprotein E immunoreactivity was found to be associatedwith neurofibrillary tangles in an autopsy study of 12 patients withprogressive supranuclear palsy (601104), the apolipoprotein E allelefrequency was similar to that of age-matched controls. Farrer et al.(Exp. Neurol. 136: 162-170, 1995) demonstrated that the number ofepsilon-4 alleles was inversely related to the age at onset of Pickdisease (172700). Their results suggested that epsilon-4 may be asusceptibility factor for dementia and not specifically for AD. Mui etal. (Ann. Neurol. 38: 460-463, 1995) found no association betweenapolipoprotein E4 and the incidence or the age of onset of sporadic ofautosomal dominant amyotrophic lateral sclerosis (105400). Garlepp etal. (Ann. Neurol. 38: 957-959, 1995) found an increased frequency of theepsilon 4 allele in patients with inclusion body myositis (147421)compared with that in patients with other inflammatory muscle diseasesor that in the general population. In a study of apoE genotypes inschizophrenic patients coming to autopsy, Harrington et al. (Neurosci.Lett. 202: 101-104, 1995) found that schizophrenia is associated with anincreased E4 allele frequency. The E4 allele frequency in schizophreniawas indistinguishable from that found in either Alzheimer disease orLewy body dementia (127750). From the age range at autopsy (from 19 to95 years), they determined that the epsilon-4 frequency was notassociated with increased age. Betard et al. (Neuroreport 5: 1893-1896,1994) analyzed allele frequencies of apoE in 166 autopsiedFrench-Canadian patients with dementia. The E4 frequency was highest inLewy body dementia (0.472); presenile Alzheimer disease (0.405); senileAlzheimer disease (0.364); and Alzheimer disease with cerebrovasculardisease (0.513). In contrast, the E4 allele frequency was 0.079 inautopsied cases of individuals with vascular dementia but no changes ofAlzheimer disease. Subjects with vascular dementia demonstrated anincreased relative E2 allele frequency of 0.211 compared to 0.144 inelderly controls. In contradistinction to the findings of Betard et al.(1994), Lippa et al. (Neurology 45: 97-103, 1995) found much lowerfrequency of E4, 0.22, when they were careful to exclude Lewy bodypatients that had concurrent Alzheimer disease by the Cerat criterion.They did, however, find that a neuritic degeneration in CA2-3 wasslightly greater in those Lewy body disease patients with the apoE4allele than those with the E3/3 genotype. Hyman et al. (Proc. Nat. Acad.Sci. 92: 3586-3590, 1995) found that senile plaques in the Alzheimerdisease of Down syndrome were abnormally large, whereas those ofAPOE4-related Alzheimer disease were unusually numerous. The findingssuggested that the pathology in Down syndrome is due to increasedamyloid production and deposition, whereas that in APOE4, disease isrelated to an increased probability of senile plaque initiation. Roystonet al. (Neuroreport 5: 2583-2585, 1994) assessed the apoE genotype inelderly Down syndrome patients and found that the epsilon-2 variant wasassociated both with increased longevity and a significantly decreasedfrequency of Alzheimer-type dementia. They noted that none of theirelderly Down patients was homozygous for the epsilon-4 allele. In acase-control study of apoE genotypes in Alzheimer disease associatedwith Down syndrome, van Gool et al. (Ann. Neurol. 38: 225-230, 1995)showed that the frequencies of apoE type 2, 3, or 4 were notsignificantly different in Down syndrome cases with Alzheimer diseasecompared with aged-matched Down syndrome controls. The apoE 4 frequencyin Down syndrome cases with Alzheimer disease was significantly lowerthan in any other Alzheimer disease populations studied thus far,suggesting that apoE4 does not significantly affect the pathogenesis ofAlzheimer disease in Down syndrome patients. Kehoe et al. (J. Med.Genet. 36: 108-111, 1999) showed that the APOE epsilon-2/epsilon-3genotype is associated with significantly earlier age of onset ofHuntington disease (143100) in males than in females. This sexdifference was not apparent for any other APOE genotypes.

[0411] Olaisen et al. (Hum. Genet. 62: 233-236, 1982) found linkage ofC3 (120700) and apoE with a lod score of 3.00 in males at arecombination fraction of 13%. Since the C3 locus is on chromosome 19,apoE can be assigned to that chromosome also. The authors stated thatpreliminary evidence suggested that the apoE locus is close to thesecretor locus (182100). Berg et al. (Cytogenet. Cell Genet. 37: 417,1984) studied apoE-C3 linkage with a C3 restriction fragment lengthpolymorphism. Low positive lod scores were found when segregation wasfrom a male (highest score at recombination fraction 0.17). Using DNAprobes, Das et al. (J. Biol. Chem. 260: 6240-6247, 1985) mapped the apoEgene to chromosome 19 by Southern blot analysis of DNA from human-rodentsomatic cell hybrids. Humphries et al. (Clin. Genet. 26: 389-396, 1984)used a common TaqI RFLP near the APOC2 gene to demonstrate close linkageto APOE in 7 families segregating for APOE protein variants. Norecombination was observed in 20 opportunities. Apparent linkagedisequilibrium was observed. On the other hand, Houlston et al. (Hum.Genet. 83: 364-368, 1989), using a robust PCR-based method for apoEgenotyping, found no strong linkage disequilibrium between the APOE andAPOC2 loci. Gedde-Dahl et al. (Hum. Genet. 67: 178-182, 1984) foundlinkage between Se and APOE with a peak lod score of 3.3 atrecombination fraction of 0.08 in males and 1.36 at 0.22 in females, andlinkage between APOE and Lu with a lod score 4.52 at zero recombination(sexes combined). The C3-APOE linkage gave lod score 4.00 at theta 0.18in males and 0.04 at theta 0.45 in females. Triply heterozygous familiesconfirmed that APOE is on the Se side and on the Lu side of C3. Lusis etal. (Proc. Nat. Acad. Sci. 83: 3929-3933, 1986) used a reciprocal wholearm translocation between the long arm of 19 and the short arm ofchromosome 1 to map APOC1, APOC2, APOE and GPI to the long arm and LDLR,C3 and PEPD to the short arm. Furthermore, they isolated a single lambdaphage that carried both APOC1 and APOE separated by about 6 kb ofgenomic DNA. Since family studies indicate close linkage of APOE andAPOC2, the 3 must be in a cluster on 19q. Because apolipoprotein E is aligand for receptors that clear remnants of chylomicrons and very lowdensity lipoproteins, lack of apoE would be expected to causeaccumulation in plasma of cholesterol-rich remnants whose prolongedcirculation should be atherogenic. Zhang et al. (Science 258: 468-471,1992) demonstrated that this was indeed the case: apoE-deficient micegenerated by gene targeting (Piedrahita et al., Proc. Nat. Acad. Sci.89:4471-4475, 1992) had 5 times normal plasma cholesterol and developedfoam cell-rich depositions in their proximal aortas by age 3 months.These spontaneous lesions progressed and caused severe occlusion of thecoronary artery ostium by 8 months. Plump et al. (Cell 71:343-353, 1992)independently found the same in apoE-deficient mice created byhomologous recombination in ES cells. The findings in the mouse modelare comparable to those in 3 human kindreds with inherited apoEdeficiency (Ghiselli et al., Science 214: 1239-1241, 1981; Mabuchi etal., Metabolism 38: 115-119, 1989; Kurosaka et al., Atherosclerosis 88:15-20, 1991). Commenting on the articles of Plump et al. (1992) andZhang et al. (1992), Brown and Goldstein (Cell 71: 187-188, 1992)pointed out that molecular genetics has given us the opportunity tosatisfy Koch's postulates for multifactorial metabolic diseases. Furtheruse of the apoE gene-targeted mice was made by Linton et al. (Science267: 1034-1037, 1995), who showed that the severe hyperlipidemia andatherosclerosis in these mice could be prevented by bone marrowtransplantation. Although the majority of apoE in plasma is of hepaticorigin, the protein is synthesized by a variety of cell types, includingmacrophages. Because macrophages derive from hematopoietic cells, bonemarrow transplantation seemed a possible therapeutic approach.ApoE-deficient mice given transplants of normal bone marrow showed apoEin the serum and a normalization of serum cholesterol levels.Furthermore, they showed virtually complete protection from diet-inducedatherosclerosis. To unravel the metabolic relationship between apoE andapoC1 in vivo, van Ree et al. (Hum. Molec. Genet. 4: 1403-1409, 1995)generated mice deficient in both apolipoproteins. This enabledsubsequent production of transgenic mice with variable ratios of normaland mutant apoE and apoC1 on a null background. They found that doubleinactivation of the ApoE and ApoC1 (107710) loci in mice, as well assingle inactivations at either one of these loci, also affected thelevels of RNA expression of other members of the Apoe-c1-c2 cluster.Homozygous Apoe-c1 knockout mice were hypercholesterolemic and, withserum cholesterol levels more than 4 times the control value, resembledmice solely deficient in apoE.

[0412] Kashyap et al. (J. Clin. Invest. 96: 1612-1620, 1995) noted thatapolipoprotein E-deficient mice, generated using homologousrecombination for targeted gene disruption in embryonic stem cells,developed marked hyperlipidemia as well as atherosclerosis. Kashyap etal. (1995) found that intravenous infusion of a recombinant adenoviruscontaining the human APOE gene resulted in normalization of the lipidand lipoprotein profile with markedly decreased total cholesterol, VLDL,IDL, and LDL, as well as increased HDL. A marked reduction in the extentof aortic atherosclerosis was observed after one month. Plump et al.(1992) and Zhang et al. (1992) created apoE-deficient mice by genetargeting in embryonic stem cells. These mice displayed severehypercholesterolemia even on a low-fat, low cholesterol diet. A keyregulator of cholesterol-rich lipoprotein metabolism, apoE, issynthesized by numerous extrahepatic tissues. It is synthesized, forexample, in macrophages. To assess the contribution ofmacrophage-derived apoE to hepatic clearance of serum cholesterol,Boisvert et al. (J. Clin. Invest. 96: 1118-1124, 1995) performed bonemarrow transplantation on hypercholesterolemic apoE-deficient ‘knockout’mice. Serum cholesterol levels dropped dramatically in the bonemarrow-treated mice largely due to a reduction in VLDL cholesterol. Theextent of atherosclerosis in the treated mice was also greatly reduced.Wildtype apoE mRNA was detected in the liver, spleen, and brain of thetreated mice indicating that gene transfer was successfully achievedthrough bone marrow transplantation. Masliah et al. (Exp. Neurol. 136:107-122, 1995) observed an age-dependent loss ofsynaptophysin-immunoreactive nerve terminals and microtubule-associatedprotein 2-immunoreactive dendrites in the neocortex and hippocampus ofapoE-deficient (knockout) mice. They suggested that apoE may play a rolein maintaining the stability of the synapto-dendritic apparatus.Sullivan et al. (J. Biol. Chem. 272: 17972-17980, 1997) found that whenthe mouse apolipoprotein E gene was replaced by the human APOE3 gene intransgenic mice, diet-induced hypercholesterolemia and atherosclerosiswere considerably enhanced. To assess the effects of human APOE isoformson deposition of amyloid-beta protein in vivo, Holtzman et al. (J. Clin.Invest. 103: R15-R21, 1999) bred apoE3 and apoE4 hemizygous(+/−)transgenic mice expressing APOE by astrocytes to mice homozygous(+/+) for a mutant amyloid precursor protein, V717F (104760.0003),transgene that developed age-dependent Alzheimer disease neuropathology.All mice had an apoE null (−/−) background. By 9 months of age, the miceheterozygous for the human V717F mutant had developed deposition ofamyloid-beta protein, and the quantity of amyloid-beta deposits wassignificantly less than that seen in heterozygous mice expressing mouseapoE. In contrast to effects of mouse apoE, similar levels of humanapoE3 and apoE4 markedly suppressed early amyloid-beta deposition at 9months of age in the V717F heterozygous transgenic mice, even whencompared with mice lacking apoE. These findings suggested that humanAPOE isoforms decrease amyloid-beta aggregation or increase amyloid-betaclearance relative to an environment in which mouse apoE or no apoE ispresent. Raber et al. (Nature 404: 352-354, 2000) tested the spatialmemory of transgenic mice carrying human forms of amyloid precursorprotein and either apoE3 or apoE4 and found that it was impaired in micewith apoE4 but not in those with apoE3, even though the levels ofbeta-amyloid in their brains were comparable. As no plaques weredetectable in APP and APP/apoE mice at 6 months of age, Raber et al.(2000) concluded that the differential effects of apoE isoforms on humanamyloid precursor protein/amyloid beta-induced cognitive impairments areindependent of plaque formation. Learning deficits were more significantin female than in male mice. These sex-dependent differences may relateto the increased susceptibility of women to APOE4-associated cognitivedeficits.

[0413] Corbo and Scacchi (Ann. Hum. Genet. 63: 301-310, 1999) analyzedthe APOE allele distribution in the world. They pointed out that theAPOE3 allele is the most frequent in all human groups, especially inpopulations with a long-established agricultural economy such as thoseof the Mediterranean basin, where the allele frequency is 0.849-0.898.The frequency of the APOE4 allele, the ancestral allele, remains higherin populations such as Pygmies (0.407) and Khoi San (0.370), aboriginesof Malaysia (0.240) and Australia (0.260), Papuans (0.368), some NativeAmericans (0.280), and Lapps (0.310) where an economy of foraging stillexists, or food supply is (or was until shortly before the time of thereport) scarce and sporadically available. The APOE2 frequencyfluctuates with no apparent trend (0.145-0.02) and is absent in NativeAmericans. Corbo and Scacchi (1999) suggested that the APOE4 allele,based on some functional properties, may be a ‘thrifty’ allele. Theexposure of APOE4 to the environmental conditions at the time of thereport (Western diet, longer lifespans) may have rendered it asusceptibility allele for coronary artery disease and Alzheimer disease.The absence of the association of APOE4 with either disorder insub-Saharan Africans, and the presence of the association in AfricanAmericans, seems to confirm this hypothesis.

[0414] In a large multicenter case control study of myocardialinfarction using 567 cases and 678 controls, Lambert et al. (Hum. Molec.Genet. 9: 57-61, 2000) identified an increased risk of myocardialinfarction among patients carrying the −219T allele, a promoterpolymorphism. The odds ratio was 1.29, with a 95% confidence interval of1.09 to 1.52 and a P value of less than 0.003. The effect of the allelewas independent of the presence of other promoter polymorphisms ormutations including the APOE epsilon-2/epsilon-3/epsilon-4 polymorphism.Moreover, the −219T allele greatly decreased the APOE plasmaconcentrations in a dose-dependent manner (P less than 0.008). Lambertet al. (2000) concluded that the −219 G-to-T polymorphism of the APOEregulatory region is a genetic susceptibility risk factor for myocardialinfarction and constitutes another common risk factor for bothneurodegenerative and cardiovascular diseases. To determine the effectof APOE on deposition of amyloid-beta and Alzheimer disease pathology,Holtzman et al. (Proc. Nat. Acad. Sci.97: 2892-2897, 2000) comparedAPP(V717F) transgenic mice expressing mouse, human, or no APOE. Asevere, plaque-associated neuritic dystrophy developed in the transgenicmice expressing mouse or human APOE. Although significant levels ofamyloid-beta deposition also occurred in APP(V717F) transgenics thatcompletely lacked APOE, neuritic degeneration was virtually absent.Expression of APOE3 and APOE4 in APP(V717F) transgenics who had knockoutof APOE resulted in fibrillar amyloid-beta deposits and neuritic plaquesby 15 months of age, and more than 10-fold more fibrillar deposits wereobserved in APOE4-expressing APP(V717F) transgenic mice. The datademonstrated a critical and isoform-specific role for APOE in neuriticplaque formation, a pathologic hallmark of Alzheimer disease.

[0415] NOV19

[0416] A disclosed NOV19 nucleic acid of 3839 nucleotides (also referredto as CG55906-01) (SEQ ID NO:57) encoding a novel S3-12-like protein isshown in Table 19A. An open reading frame was identified beginning withan ATG initiation codon at nucleotides 131-133 and ending with a TAGcodon at nucleotides 3806-3808. Putative untranslated regions upstreamfrom the initiation codon and downstream from the termination codon areunderlined and the start and stop codons are in bold in Table 19A. TABLE19A NOV19 nucleotide sequenceGTGAGGCCAGGCCTGCAGGTGGGTGTCGGGCTGCTCAGGCTTTCAGTGGGGAGTGGGTGT (SEQ IDNO:57) GGGATGGGAGGCTAGGGAACCCCCATTCACGCACCTTCTCTGCCCCCTTCCAGCTTCTCACGTTCTCACT ATGTCTGCTCCAGACGAAGGGAGACGGGATCCCCCCAAACCGAAGGGCAAGCCCCCCGCCCCCATGCAGACCCTGGGCAGCTTCTTTGGGTCCCTGCCTGGCTTCAGCTCTGCCCGGAACCTGGTGGCCAACGCACATAGCTCGGTCGGGGCCAAAGACCTGGTGTGTTCCAAGATGTCCAGGGCCAAGGATGCCGTGTCCTCCGGGGTGGCCAGCGTGGTGGACGTGGCTAAGGGAGTGGTCCAGGGAGGCCTGGACACCACTCGGTCTGCACTTACGGGCACCAAGGAGGTGGTGTCCAGCGGGGTCACAGGGGCCATGGACATGGCTAAGGGGGCCGTCCAAGGGGGTCTGGACACCTCGAAGGCTGTCCTCACCGGCACCAAGGACACGGTGTCCACTGGGCTCACGGGGGCAGTGAATGTGGCCAAAGGGACCGTACAGGCCGGTGTGGACACCACCAAGACTGTGCTGACCGGCACCAAAGACACAGTGACTACTGGGGTCATGGGGGCAGTGAACTTGGCCAAAGGGACTGTCCAGACTGGCGTGGAAACCTCCAAGGCTGTGCTGACCGGCACCAAAGATGCTGTGTCCACTGGGCTCACAGGGGCAGTGAATGTGGCCAGAGGAAGCATTCAGACCGGTGTGGACACCAGTAAGACTGTCCTAACAGGTACCAAGGACACCGTCTGTAGTGGGGTGACTGGTGCCATGAATGTGGCCAAAGGAACCATCCAGACCGGCGTGGACACCAGTAAGACTGTCCTAACAGGTACCAAGGACACCGTCTGTAGTGGGGTGACTGGTGCCATGAATGTGGCCAAAGGAACCATCCAGACCGGCGTGGACACCAGTAAGACTGTCCTAACAGGTACCAAGGACACCGTCTGTAGTGGGGTGACTGGTGCCATGAATGTGGCCAAAGGAACCATCCAGACCGGCGTGGACACCACCAAGACTGTCCTAACTGGCACCAAGAACACTGTCTGCAGTGGGGTGACCGGTGCCGTGAACTTGGCCAAAGAGGCCATCCAGGGGGGCCTGGATACCACCAAGTCTATGGTCATGGGTACGAAAGACACGATGTCCACTGGGCTCACAGGGGCAGCGAATGTGGCCAAGGGGGCCATGCAAACTGGGCTGAACACAACCCAAAATATCGCAACAGGTACAAAGGACACCGTCTGCAGTGGGGTGACTGGTGCCATGAATTTGGCCAGAGGAACCATCCAGACAGGCGTGGACACCACCAAGATCGTTCTAACTGGTACCAAGGACACTGTCTGCAGTGGGGTCACCGGTGCTGCGAATGTGGCCAAAGGGGCCGTCCAGGGCGGCCTGGACACTACAAAGTCTGTCCTGACTGGCACTAAAGATGCTGTGTCCACTGGGCTCACAGGGGCTGTGAACGTGGCCAAAGGGACCGTCCAGACCGGCGTAGACACCACCAAGACTGTCCTAACCGGCACCAAGGACACCGTCTGCAGTGGGGTGACCAGTGCTGTGAACGTGGCCAAAGGGGCCGTCCAGGGGGGCCTGGACACCACCAAGTCTGTGGTCATAGGTACAAAAGACACGATGTCCACTGGGCTCACGGGGGCAGCGAATGTGGCCAAGGGGGCTGTCCAGACAGGTGTAGACACAGCCAAGACCGTGCTGACCGGCACCAAGGACACAGTGACTACTGGGCTCGTGGGGGCAGTGAATGTCGCCAAAGGGACCGTCCAGACAGGCATGGACACCACCAAAACTGTCCTAACCGGTACCAAGGACACCATCTACAGTGGGGTCACCAGTGCCGTGAACGTGGCCAAGGGGGCTGTGCAAACTGGGCTGAAAACGACCCAAAATATCGCGACAGGTACAAAGAACACCTTTGGCAGTGGGGTGACCAGTGCTGTGAATGTGGCCAAAGGGGCTGCCCAGACAGGTGTAGACACGGCCAAGACCGTGCTGACCGGCACCAAGGACACAGTCACTACTGGGCTCATGGGGGCAGTGAATGTCGCCAAAGGGACTGTCCAGACCAGTGTGGACACCACCAAGACTGTCCTAACTGGTACCAAGGACACCGTCTGCAGTGGGGTGACCGGTGCTGCGAATGTGGCCAAAGGGGCCATCCAAGGGGGCCTGGACACTACAAAGTCTGTCCTGACTGGCACTAAAGATGCTGTGTCCACTGGGCTCACAGGGGCTGTGAAGTTGGCCAAAGGGACTGTCCAGACCGGCATGGACACCACCAAGACTGTGTTAACTGGTACCAAGGATGCTGTGTGCAGTGGGGTGACCGGTGCTGCGAATGTGGCCAAGGGGGCCGTCCAGATGGGTGTAGACACGGCCAAGACCGTGCTGACCGGTACCAAGGACACTGTCTGCAGTGGGGTCACCGGTGCTGCGAACGTGGCCAAGGGTGCTGTGCAAACTGGGCTGAAAACGACCCAAAATATCGCAACAGGTACAAAGAACACCCTTGGCAGTGGGGTGACCGGTGCTGCGAAAGTGGCCAAAGGGGCCGTCCAGGGGGGCCTGGACACTACAAAGTCTGTCCTGACTGGCACTAAAGATGCCGTGTCCACTGGGCTCACAGGGGCTGTGAACTTGGCCAAAGGGACTGTCCAGACCGGCGTGGACACCAGCAAGACTGTCCTGACCGGTACCAAGGACACCGTCTGCAGTGGAGTCACTGGTGCCGTAAATGTGGCCAAAGGGACCGTCCAGACAGGTGTGGACACAGCCAAGACGGTGCTGAGTGGCGCTAAGGATGCAGTGACTACTGGAGTCACGGGGGCAGTGAATGTGGCCAAAGGAACCGTGCAGACCGGCGTGGACGCCTCCAAGGCTGTGCTTATGGGTACCAAGGACACTGTCTTCAGTGGGGTTACCGGTGCCATGAGCATGGCCAAAGGGGCCGTCCAGGGGGGCCTGGACACCACCAAGACAGTGCTGACCGGAACCAAAGACGCAGTGTCCGCTGGGCTCATGGGGTCAGGGAACGTGGCGACAGGGGCCACCCACACTGGCCTCAGCACCTTCCAGAACTGGTTACCTAGTACCCCCGCCACCTCCTGGGGTGGACTCACCAGTTCCAGGACCACAGCTCAGCTGGCTGCCTCCCAGCCTGGGCCAAAGGTGCTGTCGGCGGAACAGGGGAGCTACTTCGTTCGTTTAGGTGACCTGGGTCCCAGCTTCCGCCAGCGGGCATTTGAACACGCGGTGAGCCACCTGCAGCACGGCCAGTTCCAAGCCAGGGACACTCTGGCCCAGCTCCAGGACTGCTTCAGGCTGATTGAAAAGGCCCAGCAGGCTCCAGAAGGGCAGCCACGTCTGGACCAGGGCTCAGGTGCCAGTGCGGAGGACGCTGCTGTCCAGGAGAGGGTCTGCGGCCTTCTCCGGCAGCTGCACACGGCCTACAGTGGCCTGGTCTCCAGCCTCCAGGGCCTGCCCGCCGAGCTCCAGCAGCCAGTGGGGCGGGCGCGGCACAGCCTCTGTGAGCTCTATGGCATCGTGGCCTCAGCTGGCTCTGTAGAGGAGCTGCCCGCAGAGCGGCTGGTGCAGAGCCGCGAGGGTGTGCACCAGGCTTGGCAGGGGTTAGAGCAGCTGCTGGAGGGCCTACAGCACAATCCCCCGCTCAGCTGGCTGGTAGGGCCCTTCGCCTTGCCCGCTGGCGGGCAGTAG CTGTAGGAGCCTGCAGGCCCGGCGCGGGGTC

[0417] The S3-12-like NOV19 disclosed in this invention maps tochromosome 19.

[0418] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 2100 of 3062 bases(68%) identical to a gb:GENBANK-ID:AF064748|acc:AF064748.1 mRNA from Musmusculus (Mus musculus S3-12 mRNA, complete cds).

[0419] A disclosed NOV19 polypeptide (SEQ ID NO:58) encoded by SEQ IDNO:57 has 1225 amino acid residues and is presented in Table 19B usingthe one-letter code. Although SignalP, Psort and/or hydropathy suggestthat the S3-12-like NOV19 protein may be localized at the cytoplasm,with a certainty of 0.4500, the protein predicted here is similar to theS3-12 family, some members of which are membrane localized. Therefore itis likely that this novel S3-12-like protein is available at the samesub-cellular localization and hence accessible to a diagnostic probe andfor various therapeutic applications. In an alternative embodiment NOV19is likely to be localized to the microbody (peroxisome) with a certaintyof 0.3000, or to the lysosome (lumen) with a certainty of 0.2966, or tothe mitochondrial matrix space with a certainty of 0.1000. TABLE 19BNOV19 protein sequenceMSAPDEGRRDPPKPKGKPPAPMQTLGSFFGSLPGFSSARNLVANAHSSVGAKDLVCSKMS (SEQ IDNO:58) RAKDAVSSGVASVVDVAKGVVQGGLDTTRSALTGTKEVVSSGVTGAMDMAKGAVQGGLDTSKAVLTGTKDTVSTGLTGAVNVAKGTVQAGVDTTKTVLTGTKDTVTTGVMGAVNLAKGTVQTGVETSKAVLTGTKDAVSTGLTGAVNVARGSIQTGVDTSKTVLTGTKDTVCSGVTGAMNVAKGTIQTGVDTSKTVLTGTKDTVCSGVTGAMNVAKGTIQTGVDTSKTVLTGTKDTVCSGVTGAMNVAKGTIQTGVDTTKTVLTGTKNTVCSGVTGAVNLAKEAIQGGLDTTKSMVMGTKDTMSTGLTGAANVAKGAMQTGLNTTQNIATGTKDTVCSGVTGAMNLARGTIQTGVDTTKIVLTGTKDTVCSGVTGAANVAKGAVQGGLDTTKSVLTGTKDAVSTGLTGAVNVAKGTVQTGVDTTKTVLTGTKDTVCSGVTSAVNVAKGAVQGGLDTTKSVVIGTKDTMSTGLTGAANVAKGAVQTGVDTAKTVLTGTKDTVTTGLVGAVNVAKGTVQTGMDTTKTVLTGTKDTIYSGVTSAVNVAKGAVQTGLKTTQNIATGTKNTFGSGVTSAVNVAKGAAQTGVDTAKTVLTGTKDTVTTGLMGAVNVAKGTVQTSVDTTKTVLTGTKDTVCSGVTGAANVAKGAIQGGLDTTKSVLTGTKDAVSTGLTGAVKLAKGTVQTGMDTTKTVLTGTKDAVCSGVTGAANVAKGAVQMGVDTAKTVLTGTKDTVCSGVTGAANVAKGAVQTGLKTTQNIATGTKNTLGSGVTGAAKVAKGAVQGGLDTTKSVLTGTKDAVSTGLTGAVNLAKGTVQTGVDTSKTVLTGTKDTVCSGVTGAVNVAKGTVQTGVDTAKTVLSGAKDAVTTGVTGAVNVAKGTVQTGVDASKAVLMGTKDTVFSGVTGAMSMAKGAVQGGLDTTKTVLTGTKDAVSAGLMGSGNVATGATHTGLSTFQNWLPSTPATSWGGLTSSRTTAQLAASQPGPKVLSAEQGSYFVRLGDLGPSFRQRAFEHAVSHLQHGQFQARDTLAQLQDCFRLIEKAQQAPEGQPRLDQGSGASAEDAAVQERVCGLLRQLHTAYSGLVSSLQGLPAELQQPVGRARHSLCELYGIVASAGSVEELPAERLVQSREGVHQAWQGLEQLLEGLQHNPPLSWLVGPFALPAGGQ

[0420] The full amino acid sequence of the protein of the invention wasfound to have 721 of 1199 amino acid residues (60%) identical to, and898 of 1199 amino acid residues (74%) similar to, the 1403 amino acidresidue ptnr:SPTREMBL-ACC:088492 protein from Mus musculus (Mouse)(S3-12).

[0421] In a search of public sequence databases, NOV19 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 19C. TABLE 19C BLASTP results for NOV19 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expectptnr:SPTREMBL- KIAA1881 PROTEIN - 1348 875/993 922/993 0.0 ACC:Q96Q06Homo sapiens (88%) (92%) ptnr:SPTREMBL- S3-12 - Mus musculus 1403721/1199 898/1199 0.0 ACC:088492 (60%) (74%) ptnr:SPTREMBL- HYPOTHETICAL3145 361/969 406/969 7.9e-74 ACC:Q98MG7 GLYCINE - (37%) (41%) RICHPROTEIN MLR0587 - Rhizobium loti (Mesorhizobium loti) ptnr:SPTREMBL-HYPOTHETICAL 2147 353/944 401/944 3.5e-69 ACC:Q98MG8 GLYCINE- (37%)(42%) RICH PROTEIN MLR0585 - Rhizobium loti (Mesorhizobium loti)ptnr:SPTREMBL- HYPOTHETICAL 119.8 1195 248/844 332/844 1.0e-42ACC:Q96WU8 KDA PROTEIN - (29%) (39%) Schizosaccharomyces pombe (Fissionyeast)

[0422] A multiple sequence alignment is shown in Table 19D, with theprotein of the invention being shown on line one in a ClustalW analysiscomparing the protein of the invention with related protein sequencesshown in Table 19C.

[0423] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 19E. TABLE 19E Patp BLASTP Analysis for NOV19 Sequences producingHigh- scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp: AAY95851 Autoantigen diagnostic of 439431/436 432/436 3.8e−220 endometriosis - Homo (98%) (99%) sapiens patp:AAY44931 Mammalian adipose 286 192/200 192/200 9.7e−99 differentiationassociated (96%) (96%) protein - Mammalia patp: AAY48492 Human breasttumour- 324 225/324 239/324 9.4e−98 associated protein 37 - (69%) (73%)Homo sapiens patp: AAY44929 Human adipose 213 192/200 192/200 6.6e−97differentiation associated (96%) (96%) protein-1 - Homo sapiens patp:AAY44930 Human adipose 206 192/200 192/200 6.6e−97 differentiationassociated (96%) (96%) protein-2 - Homo sapiens

[0424] Significant domains of NOV19 are summarized in Table 19F. TABLE19F Domain Analysis of NOV19 Pfam analysis Model Domain seq-f seq-thmm-f hmm-t score E-value LEA 1/4 46 115 .. 1 75 [ ] 18.5 0.085 LEA 2/4306 379 .. 1 75 [ ] 1.1 2 LEA 3/4 475 548 .. 1 75 [ ] 5.1 0.96 LEA 4/4772 863 .. 1 75 [ ] −1.3 3 perilipin 1/1 844 1209 ..  1 411 [ ]  −20.10.00018 Alignments of top-scoring domains: LEA: domain 1 of 4, from 46to 115: score 18.5, E = 0.085 (SEQ ID NO:235)ekAketadsAkekAseakdaakdEAeeAkdaakeEAeeAkdkakekk +   ++| +  |+| ||||+   ++ + | ||   ++  |++  + NOV19 46HSSVGAKDLVCSKMSRAKDAVSSGVASVVDVAKGVVQGGLDTTRSA- 91ageaKDktgnkakekaeeaKdkasdakd < -*    +|+    ++++    |+|+|++|++ 92LTGTKE----VVSSGVTGAMDMAKGAVQ 115 LEA: domain 2 of 4, from 306 to 379:score 1.1, E = 2 (SEQ ID NO:236)ekAketadsAkekAse....akdaakdKAeeAkdaakeKAeeAkdka  || | ++  ++++   +++ +++   + +| + |||+ ++  |++ NOV19 306NVAKGTIQTGVDTTKTvltgTKNTVCSGVTGAVNLAKEAIQGGLDTT 352kekkageaKDktgnkakekaeeaKdkasdakd < -* |   +  +||    + +     | + |++|++353 KSM-VMGTKD----TMSTGLTGAANVAKGAMQ 379 LEA: domain 3 of 4, from 475 to548: score 5.1, E = 0.96 (SEQ ID NO:237)ekAketadsAkekAseakdaakdKAeeAkdaakeKAeeAkdkakekk++++   |++|     +||++   +  | + || + ++  |++| NOV19 475GTVQTGVDTTKTVLTGTKDTVCSGVTSAVNVAKGAVQGGLDTTKSV- 520ageaKDktg.nkakekaeeaKdkasdakd < -* +  +||+++++ + ++|  ||++++  +| 521VIGTKDTMStGLT-GAANVAKGAVQTGVD 548 LEA: domain 4 of 4, from 772 to 863:score −1.3, E = 3 (SEQ ID NO:238)ekAketadsAkekAseakdaakdKAeeAkdaakeEAee.........++++   |+||     +||++   + +|++ || + + + +++++ NOV19 772GAVQMGVDTAKTVLTGTKDTVCSGVTGAANVAKGAVQTglkttqnia 818.............AkdkakekkageaKDktgnkakekaeeaKdkasdakd++++++ +++ ++|+  ||++ ++ + |    ++|++   +||++| 819tgtkntlgsgvtgAAKVAKGA-VQGGLD----TTKSVLTGTKDAVSTGLT 863 perilipin: domain1 of 1, from 844 to 1209: score −20.1, E = 0.00018 (SEQ ID NO:239)matavedlpqqesVvd..RvasLPlVsstikcdlVsaaYdstKenyp+ |+ + |   +++| +++ +   |  +|     |++  | +| + NOV19 844LDTTKSVLTGTKDAVStgLTGAVNLAKGT-----VQTGVDTSKTVLT 885lvkGvksVceaaekGvetitsaAvtsaqPivkkLepqIavaneyackGLD    + +||     || +++++|  ++|       +    | +++    | 886G--TKDTVC----SGVTGAVNVAKGTVQ-------TGVDTAKTVLSGAKD 922kLEeklPiLqqPpekivanaKgavtgakdavstrvesakdsVvqpilerv       ++    +  |+ ||| |   +||    + + ||+| + +++++ 923-------AVTTGVTGAVNVAKGTVQTGVDASKAVLMGTKDTVFSGVTGAM 965DkvKgAvqagvEstKsvvtgsantVlgsrvgqlassGVDt.aLgksEklv   |||||+|++ || | ||+   | +   | ++|+ | |+|+ + 966SMAKGAVQGGLDTTKTVLTGTKDAVSA---GLMGSGNVATgATHTGLSTF 1012eqylP.............pteeElekeAkkvegfDskkvqqqrqkp.sal + ||+++ ++ ++ +++ | + |+   +++ |+++ +     ++++|++ 1013QNWLPstpatswggltssRTTAQLA---ASQPGPKVLS-----AEQgSYF 1054vrlgslSekLrrrayqqalgrvraaKqrSqeaihqLqsvaeLietakkgv|||| |    |+|| ++|++ ++ +  ++  +++|||  ++|||+|++ 1055VRLGDLGPSFRQRAFEHAVSHLQHGQFQARDTLAQLQDCFRLIEKAQQAP 1104sqanqkvsraqdkLyvlWlewkassgedpedesdtepeqiEsrilll.tr                              |++   ++  |  ++ ++ 1105EGQPR------------------------LDQGS--GASAEDAAVQErVC 1128elaqqlvaalktllssiqgipqnlqdtvqqvgsmsgdaysafrsraasfk |++|| +|  +|+||+||+|  ||  | +++ +  ++|  + | | | 1129GLLRQLHTAYSGLVSSLQGLPAELQQPVGRARHSLCELYGIVAS-AGSVE 1177etsdglltsskgrvaslkealdevmdyvVsnt < -* |+++  | +|++ |  +  +|    + +  |1178 ELPAERLVQSREGVHQAWQGLEQLLEGLQHNP 1209

[0425] The S3-12 disclosed in this invention is expressed in at leastthe following tissues: colon, lung. In addition, the sequence ispredicted to be expressed in the following tissues because of theexpression pattern of (GENBANK-ID:gb:GENBANK-ID:AF0647481acc:AF064748.1) a closely related Mus musculusS3-12 mRNA, complete cds homolog in species Mus musculus adipocytes.

[0426] The nucleic acids and proteins of the invention are useful inpotential diagnostic and therapeutic applications implicated in variousdiseases and disorders described below and/or other pathologies. Forexample, the compositions of the present invention will have efficacyfor treatment of patients suffering from: cancer, trauma, regeneration(in vitro and in vivo), viral/bacterial/parasitic infections,Hirschsprung's disease, Crohn's Disease, appendicitis, systemic lupuserythematosus, autoimmune disease, asthma, emphysema, scleroderma,allergy, ARDS and other diseases, disorders and conditions of the like.

[0427] This novel human protein has best homology to a novel mouseprotein S3-12 cloned from mouse adipocytes using an antibody basedsubtractive hybridization protocol. It also contains tandem repeats of athreonine-rich 33-amino acid motif; which are similar to 33-amino acidmotif in adipocyte differentiation-related protein (ADRP).

[0428] This sequence has 99% homology to a patented partial cDNA, Acc NoA50242, that has been described as encoding an autoantigen diagnostic ofendometriosis (see Y95851). These autoantigens (see Y95843-55) can beused in non-invasive assays to detect endometriosis. The assays arebased on the binding of the autoantigens by autoantibodies in a bodyfluid of a patient. The autoantigens may be immobilized on solidsupports and used in an immunoprecipitation assay, an enzyme linkedimmunosorbant assay (ELISA), a depletion enzyme-linked immunosorbantassay (dELISA), a Western blot, a particle agglutination assay, aluminescent oxygen-channeling immunoassay, a proximity-basedimmunosorbant assay and/or a biosensor-based immunoassay to detect thepresence of autoantibodies immunospecific for them. The presence of suchantibodies is indicative of the presence of endometriosis. High clinicalsensitivity and specificity, as well as a means for assessing diseaseprogression, prognosis and therapeutic efficacy, are achieved.Polynucleotides encoding the autoantigens can be used in the recombinantproduction of the autoantigens.

[0429] NOV20

[0430] A disclosed NOV20 nucleic acid of 810 nucleotides (also referredto as CG55906-02) (SEQ ID NO:59) encoding a novel S3-12-like protein isshown in Table 20A. An open reading frame was identified beginning withan ATG initiation codon at nucleotides 123-125 and ending with a TGAcodon at nucleotides 792-794. Putative untranslated regions upstreamfrom the initiation codon and downstream from the termination codon areunderlined. The start and stop codons are in bold in Table 20A. TABLE20A NOV20 nucleotide sequenceAGGCCTGCAGGTGGGTGTCGGGCTGCTCAGGCTTTCAGTGGGGAGTGGGTGTGGGATGGG (SEQ IDNO:59) AGGCTAGGGAACCCCCATTCACGCACCTTCTCTGCCCCCTTCCAGCTTCTCACGTTCTCA CTATGTCTGCTCCAGACGAAGGGAGACGGGATCCCCCCAAACCGAAGGGCAAGACCCTGGGCAGCTTCTTTGGGTCCCTGCCTGGCTTCAACTCTGCCCGGAACCTGGTGGCCAACGCACATAGCTCGGCGAGAGCCCGGCCGGCCGCTGACCCCACAGGAGCGCCTGCTGCCGAGGCTGCCCAACCACAGGCTCAGGTGGCTGCCCACCCAGAGCAGACGGCCCCATGGACGGAGAAGGAGCTGCAACCTTCGGAAAAGATTGAAAAGGCCCAGCAGGCTCCAGAAGGGCAGCCACGTCTGGACCAGGGCTCAGGTGCCAGTGCGGAGGACGCTGCTGTCCAGGAGGAGCGGGATGCCGGGGTTCTGTCCAGGGTCTGCGGCCTTCTCCGGCAGCTGCACACGGCCTACAGTGGCCTGGTCTCCAGCCTCCGGGGCCTGCCCGCCGAGCTCCAGCAGCCAGTGGGGCGGGCGCGGCACAGCCTCTGTGAGCTCTATGGCATCGTGGCCTCAGCTGGCTCTGTAGAGGAGCTGCCCGCAGAGCGGCTGGTGCAGAGCCGCGAGGGTGTGCACCAGGCTTGGCAGGGGTTAGAGCAGCTGCTGGAGGGCCTACAGCACAATCCCCCGCTCAGCTGGCTGGTAGGGCCCTTCGCCTTGCCCGCTGGCGGGCAGTAG CTGTAGGAGCCTGCAG

[0431] The S3-12-like NOV20 gene disclosed in this invention maps tochromosome 19.

[0432] In a search of sequence databases, it was found, for example,that the nucleic acid sequence of this invention has 349 of 526 bases(66%) identical to a gb:GENBANK-ID:AF064748|acc:AF064748.1 mRNA from Musmusculus (Mus musculus S3-12 mRNA, complete cds).

[0433] A disclosed NOV20 polypeptide (SEQ ID NO:60) encoded by SEQ IDNO:59 has 223 amino acid residues and is presented in Table 20B usingthe one-letter code. The SignalP, Psort and/or Hydropathy resultspredict that NOV20 has no signal peptide and is likely to be localizedin the cytoplasm with a certainty of 0.6500 predicted by PSORT. Theprotein of this invention may be membrane-associated, based on itshomology to mouse S3-12 (Nat Biotechnol June 1998;16(6):581-6). In analternative embodiment, NOV20 is likely to be localized to the lysosome(lumen) with a certainty of 0.1916, or to the mitochondrial matrix spacewith a certainty of 0.1000. TABLE 20B NOV20 protein sequenceMSAPDEGRRDPPKPKGKTLGSFFGSLPGFNSARNLVANAHSSARARPAADPTGAPAAEAA (SEQ IDNO:60) QPQAQVAAHPEQTAPWTEKELQPSEKIEKAQQAPEGQPRLDQGSGASAEDAAVQEERDAGVLSRVCGLLRQLHTAYSGLVSSLRGLPAELQQPVGRARHSLCELYGIVASAGSVEELPAERLVQSREGVHQAWQGLEQLLEGLQHNPPLSWLVGPFALPAGGQ

[0434] NOV19 and NOV20 are both members of the S3-12 protein family andhave similar protein sequence at the N-terminus and C-terminus. Therelationship between the NOV19 and NOV20 protein sequences is shown inTable 20C.

[0435] The full amino acid sequence of the NOV20 protein of theinvention was found to have 75 of 142 amino acid residues (52%)identical to, and 94 of 142 amino acid residues (66%) similar to, the1403 amino acid residue ptnr:SPTREMBL-ACC:088492 protein from Musmusculus (Mouse) (S3-12).

[0436] In a search of public sequence databases, NOV20 was found to havehomology to the amino acid sequences shown in the BLASTP data listed inTable 20D. TABLE 20D BLASTP results for NOV20 Gene Index/ LengthIdentity Positives Identifier Protein/Organism (aa) (%) (%) Expect ptnr:SPTREMBL- KIAA1881 PROTEIN - 1348 141/156 145/156 1.6e−67 ACC: Q96Q06Homo sapiens (90%) (92%) ptnr: SPTREMBL- S3-12 - Mus musculus 1403 75/142 9 4/142 9.9e−28 ACC: O88492 (52%) (66%) ptnr: SWISSPROT- Cargoselection 434  55/197  95/197 3.5e−10 ACC: O60664 protein TIP47 (47 kDa(27%) (48%) mannose 6-phosphate receptor - binding protein) (47 kDa MPR-binding protein) (Placental protein 17) - Homo sapiens ptnr: SPTREMBL-CARGO SELECTION 434  55/197  95/197 3.5e−10 ACC: Q9BS03 PROTEIN (MANNOSE6 (27%) (48%) PHOSPHATE RECEPTOR BINDING PROTEIN) - Homo sapiens ptnr:SPTREMBL- 1300012C15RIK PROTEIN 437  46/145  75/145 2.4e−09 ACC: Q9DBG5(RIKEN CDNA 1300012C15 (31%) (51%) GENE) - Mus musculus

[0437] A multiple sequence alignment is shown in Table 20E, with theproteins of the invention being shown on lines one and two in a ClustalWanalysis comparing the protein of the invention with related proteinsequences shown in Table 20D.

[0438] Other BLAST results include sequences from the Patp database,which is a proprietary database that contains sequences published inpatents and patent publications. Patp results include those listed inTable 20F. TABLE 20F Patp BLASTP Analysis for NOV20 Sequences producingHigh-scoring Segment Length Identity Positive Pairs Protein/Organism(aa) (%) (%) E Value patp: Human breast 324 141/156 145/156 1.0e−68AAY48492 tumour-associated (90%) (92%) protein 37 - Homo sapiens patp:Human adipose 213 141/156 145/156 1.0e−68 AAY44929 differentiation (90%)(92%) associated protein-1 - Homo sapiens patp: Human adipose 206141/156 145/156 1.0e−68 AAY44930 differentiation (90%) (92%) associatedprotein-2 - Homo sapiens patp: Mammalian adipose 286 141/156 145/1561.0e−68 AAY44931 differentiation (90%) (92%) associated protein -Mammalia patp: Human adipophilin- 434  55/197  95/197 2.7e−10 AAY67240like protein (27%) (48%) (HALP) amino acid sequence - Homo sapiens

[0439] Table 20G lists the domain description from DOMAIN analysisresults against NOV20. TABLE 20F Domain Analysis of NOV20 Pfam analysisModel Domain seq-f seq-t hmm-f hmm-t score E-value [no hits abovethresholds]

[0440] The S3-12-like gene disclosed in this invention is expressed inat least the following tissues: adrenal gland, bone marrow,brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantianigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetalliver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland,pancreas, pituitary gland, placenta, prostate, salivary gland, skeletalmuscle, small intestine, spinal cord, spleen, stomach, testis, thyroid,trachea, uterus, liver.

[0441] The sequence is predicted to be expressed in adipocytes becauseof the expression pattern of (GENBANK-ID:gb:GENBANK-ID:AF064748|acc:AF064748.1) a closely related Mus musculusS3-12 mRNA, complete cds homolog in species Mus musculus.

[0442] The nucleic acids and proteins of the invention haveapplicationsin the diagnosis and/or treatment of various diseases anddisorders. For example, the compositions of the present invention mayhave efficacy for the treatment of patients suffering from obesity aswell as other diseases, disorders and conditions. This novel humanprotein has best homology to a novel mouse protein S3-12 cloned frommouse adipocytes using an antibody based subtractive hybridizationprotocol. S3-12 contains tandem repeats of a threonine-rich 33-aminoacid motif; which are similar to 33-amino acid motif in adipocytedifferentiation-related protein (ADRP). Therefore the protein of thisinvention may be useful in the treatment of obesity and itscomplications, such as hypertension, diabetes.

[0443] This novel human protein has best homology to a novel mouseprotein S3-12 cloned from mouse adipocytes using an antibody basedsubtractive hybridization protocol. It also contains tandem repeats of athreonine-rich 33-amino acid motif; which are similar to 33-amino acidmotif in adipocyte differentiation-related protein (ADRP).

[0444] This sequence has 99% homology to a patented partial cDNA, Acc NoA50242, that has been described as encoding an autoantigen diagnostic ofendometriosis (see Y95851). These autoantigens (see Y95843-55) can beused in non-invasive assays to detect endometriosis. The assays arebased on the binding of the autoantigens by autoantibodies in a bodyfluid of a patient. The autoantigens may be immobilized on solidsupports and used in an immunoprecipitation assay, an enzyme linkedimmunosorbant assay (ELISA), a depletion enzyme-linked immunosorbantassay (dELISA), a Western blot, a particle agglutination assay, aluminescent oxygen-channeling immunoassay, a proximity-basedimmunosorbant assay and/or a biosensor-based immunoassay to detect thepresence of autoantibodies immunospecific for them. The presence of suchantibodies is indicative of the presence of endometriosis. High clinicalsensitivity and specificity, as well as a means for assessing diseaseprogression, prognosis and therapeutic efficacy, are achieved.Polynucleotides encoding the autoantigens can be used in the recombinantproduction of the autoantigens.

[0445] NOVX Nucleic Acids and Polypeptides

[0446] One aspect of the invention pertains to isolated nucleic acidmolecules that encode NOVX polypeptides or biologically active portionsthereof. Also included in the invention are nucleic acid fragmentssufficient for use as hybridization probes to identify NOVX-encodingnucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR primersfor the amplification and/or mutation of NOVX nucleic acid molecules. Asused herein, the term “nucleic acid molecule” is intended to include DNAmolecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA),analogs of the DNA or RNA generated using nucleotide analogs, andderivatives, fragments and homologs thereof. The nucleic acid moleculemay be single-stranded or double-stranded, but preferably is compriseddouble-stranded DNA.

[0447] An NOVX nucleic acid can encode a mature NOVX polypeptide. Asused herein, a “mature” form of a polypeptide or protein disclosed inthe present invention is the product of a naturally occurringpolypeptide or precursor form or proprotein. The naturally occurringpolypeptide, precursor or proprotein includes, by way of nonlimitingexample, the full-length gene product, encoded by the correspondinggene. Alternatively, it may be defined as the polypeptide, precursor orproprotein encoded by an ORF described herein. The product “mature” formarises, again by way of nonlimiting example, as a result of one or morenaturally occurring processing steps as they may take place within thecell, or host cell, in which the gene product arises. Examples of suchprocessing steps leading to a “mature” form of a polypeptide or proteininclude the cleavage of the N-terminal methionine residue encoded by theinitiation codon of an ORF, or the proteolytic cleavage of a signalpeptide or leader sequence. Thus a mature form arising from a precursorpolypeptide or protein that has residues 1 to N, where residue 1 is theN-terminal methionine, would have residues 2 through N remaining afterremoval of the N-terminal methionine. Alternatively, a mature formarising from a precursor polypeptide or protein having residues 1 to N,in which an N-terminal signal sequence from residue 1 to residue M iscleaved, would have the residues from residue M+1 to residue Nremaining. Further as used herein, a “mature” form of a polypeptide orprotein may arise from a step of post-translational modification otherthan a proteolytic cleavage event. Such additional processes include, byway of non-limiting example, glycosylation, myristoylation orphosphorylation. In general, a mature polypeptide or protein may resultfrom the operation of only one of these processes, or a combination ofany of them. The term “probes”, as utilized herein, refers to nucleicacid sequences of variable length, preferably between at least about 10nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt,depending upon the specific use. Probes are used in the detection ofidentical, similar, or complementary nucleic acid sequences. Longerlength probes are generally obtained from a natural or recombinantsource, are highly specific, and much slower to hybridize thanshorter-length oligomer probes. Probes may be single- or double-strandedand designed to have specificity in PCR, membrane-based hybridizationtechnologies, or ELISA-like technologies.

[0448] The term “isolated” nucleic acid molecule, as utilized herein, isone, which is separated from other nucleic acid molecules which arepresent in the natural source of the nucleic acid. Preferably, an“isolated” nucleic acid is free of sequences which naturally flank thenucleic acid (i.e., sequences located at the 5′- and 3′-termini of thenucleic acid) in the genomic DNA of the organism from which the nucleicacid is derived. For example, in various embodiments, the isolated NOVXnucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flankthe nucleic acid molecule in genomic DNA of the cell/tissue from whichthe nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.).Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule,can be substantially free of other cellular material or culture mediumwhen produced by recombinant techniques, or of chemical precursors orother chemicals when chemically synthesized.

[0449] A nucleic acid molecule of the invention, e.g., a nucleic acidmolecule having the nucleotide sequence SEQ ID NOS: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47,49, 51, 53, 55, 57, and 59, or a complement of this aforementionednucleotide sequence, can be isolated using standard molecular biologytechniques and the sequence information provided herein. Using all or aportion of the nucleic acid sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47,49, 51, 53, 55, 57, and 59 as a hybridization probe, NOVX molecules canbe isolated using standard hybridization and cloning techniques (e.g.,as described in Sambrook, et al., (eds.), MOLECULAR CLONING: ALABORATORY MANUAL 2^(nd) Ed., Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 1989; and Ausubel, et al., (eds.), CURRENTPROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y.,1993.)

[0450] A nucleic acid of the invention can be amplified using cDNA, mRNAor alternatively, genomic DNA, as a template and appropriateoligonucleotide primers according to standard PCR amplificationtechniques. The nucleic acid so amplified can be cloned into anappropriate vector and characterized by DNA sequence analysis.Furthermore, oligonucleotides corresponding to NOVX nucleotide sequencescan be prepared by standard synthetic techniques, e.g., using anautomated DNA synthesizer.

[0451] As used herein, the term “oligonucleotide” refers to a series oflinked nucleotide residues, which oligonucleotide has a sufficientnumber of nucleotide bases to be used in a PCR reaction. A shortoligonucleotide sequence may be based on, or designed from, a genomic orcDNA sequence and is used to amplify, confirm, or reveal the presence ofan identical, similar or complementary DNA or RNA in a particular cellor tissue. Oligonucleotides comprise portions of a nucleic acid sequencehaving about 10 nt, 50 nt, or 100 nt in length, preferably about 15 ntto 30 nt in length. In one embodiment of the invention, anoligonucleotide comprising a nucleic acid molecule less than 100 nt inlength would further comprise at least 6 contiguous nucleotides SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, or a complementthereof. Oligonucleotides may be chemically synthesized and may also beused as probes.

[0452] In another embodiment, an isolated nucleic acid molecule of theinvention comprises a nucleic acid molecule that is a complement of thenucleotide sequence shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53,55, 57, and 59, or a portion of this nucleotide sequence (e.g., afragment that can be used as a probe or primer or a fragment encoding abiologically-active portion of an NOVX polypeptide). A nucleic acidmolecule that is complementary to the nucleotide sequence shown SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, or 59 is one that issufficiently complementary to the nucleotide sequence shown SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37,39, 41, 43, 45, 47, 49, 51, 53, 55, 57, or 59 that it can hydrogen bondwith little or no mismatches to the nucleotide sequence shown SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, or 59, thereby forming astable duplex.

[0453] As used herein, the term “complementary” refers to Watson-Crickor Hoogsteen base pairing between nucleotides units of a nucleic acidmolecule, and the term “binding” means the physical or chemicalinteraction between two polypeptides or compounds or associatedpolypeptides or compounds or combinations thereof. Binding includesionic, non-ionic, van der Waals, hydrophobic interactions, and the like.A physical interaction can be either direct or indirect. Indirectinteractions may be through or due to the effects of another polypeptideor compound. Direct binding refers to interactions that do not takeplace through, or due to, the effect of another polypeptide or compound,but instead are without other substantial chemical intermediates.

[0454] Fragments provided herein are defined as sequences of at least 6(contiguous) nucleic acids or at least 4 (contiguous) amino acids, alength sufficient to allow for specific hybridization in the case ofnucleic acids or for specific recognition of an epitope in the case ofamino acids, respectively, and are at most some portion less than a fulllength sequence. Fragments may be derived from any contiguous portion ofa nucleic acid or amino acid sequence of choice. Derivatives are nucleicacid sequences or amino acid sequences formed from the native compoundseither directly or by modification or partial substitution. Analogs arenucleic acid sequences or amino acid sequences that have a structuresimilar to, but not identical to, the native compound but differs fromit in respect to certain components or side chains. Analogs may besynthetic or from a different evolutionary origin and may have a similaror opposite metabolic activity compared to wild type. Homologs arenucleic acid sequences or amino acid sequences of a particular gene thatare derived from different species. Derivatives and analogs may be fulllength or other than full length, if the derivative or analog contains amodified nucleic acid or amino acid, as described below. Derivatives oranalogs of the nucleic acids or proteins of the invention include, butare not limited to, molecules comprising regions that are substantiallyhomologous to the nucleic acids or proteins of the invention, in variousembodiments, by at least about 70%, 80%, or 95% identity (with apreferred identity of 80-95%) over a nucleic acid or amino acid sequenceof identical size or when compared to an aligned sequence in which thealignment is done by a computer homology program known in the art, orwhose encoding nucleic acid is capable of hybridizing to the complementof a sequence encoding the aforementioned proteins under stringent,moderately stringent, or low stringent conditions. See e.g. Ausubel, etal., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NewYork, N.Y., 1993, and below.

[0455] A “homologous nucleic acid sequence” or “homologous amino acidsequence,” or variations thereof, refer to sequences characterized by ahomology at the nucleotide level or amino acid level as discussed above.Homologous nucleotide sequences encode those sequences coding forisoforms of NOVX polypeptides. Isoforms can be expressed in differenttissues of the same organism as a result of, for example, alternativesplicing of RNA. Alternatively, isoforms can be encoded by differentgenes. In the invention, homologous nucleotide sequences includenucleotide sequences encoding for an NOVX polypeptide of species otherthan humans, including, but not limited to: vertebrates, and thus caninclude, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and otherorganisms. Homologous nucleotide sequences also include, but are notlimited to, naturally occurring allelic variations and mutations of thenucleotide sequences set forth herein. A homologous nucleotide sequencedoes not, however, include the exact nucleotide sequence encoding humanNOVX protein. Homologous nucleic acid sequences include those nucleicacid sequences that encode conservative amino acid substitutions (seebelow) in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27,29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, aswell as a polypeptide possessing NOVX biological activity. Variousbiological activities of the NOVX proteins are described below.

[0456] An NOVX polypeptide is encoded by the open reading frame (“ORF”)of an NOVX nucleic acid. An ORF corresponds to a nucleotide sequencethat could potentially be translated into a polypeptide. A stretch ofnucleic acids comprising an ORF is uninterrupted by a stop codon. An ORFthat represents the coding sequence for a full protein begins with anATG “start” codon and terminates with one of the three “stop” codons,namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF maybe any part of a coding sequence, with or without a start codon, a stopcodon, or both. For an ORF to be considered as a good candidate forcoding for a bona fide cellular protein, a minimum size requirement isoften set, e.g., a stretch of DNA that would encode a protein of 50amino acids or more.

[0457] The nucleotide sequences determined from the cloning of the humanNOVX genes allows for the generation of probes and primers designed foruse in identifying and/or cloning NOVX homologues in other cell types,e.g. from other tissues, as well as NOVX homologues from othervertebrates. The probe/primer typically comprises substantially purifiedoligonucleotide. The oligonucleotide typically comprises a region ofnucleotide sequence that hybridizes under stringent conditions to atleast about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutivesense strand nucleotide sequence SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15,17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51,53, 55, 57, or 59; or an anti-sense strand nucleotide sequence of SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, or 59; or of a naturallyoccurring mutant of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57,and 59.

[0458] Probes based on the human NOVX nucleotide sequences can be usedto detect transcripts or genomic sequences encoding the same orhomologous proteins. In various embodiments, the probe further comprisesa label group attached thereto, e.g. the label group can be aradioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.Such probes can be used as a part of a diagnostic test kit foridentifying cells or tissues which mis-express an NOVX protein, such asby measuring a level of an NOVX-encoding nucleic acid in a sample ofcells from a subject e.g., detecting NOVX mRNA levels or determiningwhether a genomic NOVX gene has been mutated or deleted.

[0459] “A polypeptide having a biologically-active portion of an NOVXpolypeptide” refers to polypeptides exhibiting activity similar, but notnecessarily identical to, an activity of a polypeptide of the invention,including mature forms, as measured in a particular biological assay,with or without dose dependency. A nucleic acid fragment encoding a“biologically-active portion of NOVX” can be prepared by isolating aportion SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27,29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, or 59, thatencodes a polypeptide having an NOVX biological activity (the biologicalactivities of the NOVX proteins are described below), expressing theencoded portion of NOVX protein (e.g., by recombinant expression invitro) and assessing the activity of the encoded portion of NOVX.

[0460] NOVX Nucleic Acid and Polypeptide Variants

[0461] The invention further encompasses nucleic acid molecules thatdiffer from the nucleotide sequences shown in SEQ ID NOS: 1, 3, 5, 7, 9,11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45,47, 49, 51, 53, 55, 57, and 59 due to degeneracy of the genetic code andthus encode the same NOVX proteins as that encoded by the nucleotidesequences shown in SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57,and 59. In another embodiment, an isolated nucleic acid molecule of theinvention has a nucleotide sequence encoding a protein having an aminoacid sequence shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56,58, or 60.

[0462] In addition to the human NOVX nucleotide sequences shown in SEQID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33,35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, it will beappreciated by those skilled in the art that DNA sequence polymorphismsthat lead to changes in the amino acid sequences of the NOVXpolypeptides may exist within a population (e.g., the human population).Such genetic polymorphism in the NOVX genes may exist among individualswithin a population due to natural allelic variation. As used herein,the terms “gene” and “recombinant gene” refer to nucleic acid moleculescomprising an open reading frame (ORF) encoding an NOVX protein,preferably a vertebrate NOVX protein. Such natural allelic variationscan typically result in 1-5% variance in the nucleotide sequence of theNOVX genes. Any and all such nucleotide variations and resulting aminoacid polymorphisms in the NOVX polypeptides, which are the result ofnatural allelic variation and that do not alter the functional activityof the NOVX polypeptides, are intended to be within the scope of theinvention.

[0463] Moreover, nucleic acid molecules encoding NOVX proteins fromother species, and thus that have a nucleotide sequence that differsfrom the human SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23,25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and59 are intended to be within the scope of the invention. Nucleic acidmolecules corresponding to natural allelic variants and homologues ofthe NOVX cDNAs of the invention can be isolated based on their homologyto the human NOVX nucleic acids disclosed herein using the human cDNAs,or a portion thereof, as a hybridization probe according to standardhybridization techniques under stringent hybridization conditions.

[0464] Accordingly, in another embodiment, an isolated nucleic acidmolecule of the invention is at least 6 nucleotides in length andhybridizes under stringent conditions to the nucleic acid moleculecomprising the nucleotide sequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49,51, 53, 55, 57, and 59. In another embodiment, the nucleic acid is atleast 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or morenucleotides in length. In yet another embodiment, an isolated nucleicacid molecule of the invention hybridizes to the coding region. As usedherein, the term “hybridizes under stringent conditions” is intended todescribe conditions for hybridization and washing under which nucleotidesequences at least 60% homologous to each other typically remainhybridized to each other.

[0465] Homologs (i.e., nucleic acids encoding NOVX proteins derived fromspecies other than human) or other related sequences (e.g., paralogs)can be obtained by low, moderate or high stringency hybridization withall or a portion of the particular human sequence as a probe usingmethods well known in the art for nucleic acid hybridization andcloning.

[0466] As used herein, the phrase “stringent hybridization conditions”refers to conditions under which a probe, primer or oligonucleotide willhybridize to its target sequence, but to no other sequences. Stringentconditions are sequence-dependent and will be different in differentcircumstances. Longer sequences hybridize specifically at highertemperatures than shorter sequences. Generally, stringent conditions areselected to be about 5° C. lower than the thermal melting point (Tm) forthe specific sequence at a defined ionic strength and pH. The Tm is thetemperature (under defined ionic strength, pH and nucleic acidconcentration) at which 50% of the probes complementary to the targetsequence hybridize to the target sequence at equilibrium. Since thetarget sequences are generally present at excess, at Tm, 50% of theprobes are occupied at equilibrium. Typically, stringent conditions willbe those in which the salt concentration is less than about 1.0 M sodiumion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0to 8.3 and the temperature is at least about 30° C. for short probes,primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about60° C. for longer probes, primers and oligonucleotides. Stringentconditions may also be achieved with the addition of destabilizingagents, such as formamide.

[0467] Stringent conditions are known to those skilled in the art andcan be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULARBIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, theconditions are such that sequences at least about 65%, 70%, 75%, 85%,90%, 95%, 98%, or 99% homologous to each other typically remainhybridized to each other. A non-limiting example of stringenthybridization conditions are hybridization in a high salt buffercomprising 6×SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02%Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65° C.,followed by one or more washes in 0.2×SSC, 0.01% BSA at 50° C. Anisolated nucleic acid molecule of the invention that hybridizes understringent conditions to the sequences SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49,51, 53, 55, 57, and 59, corresponds to a naturally-occurring nucleicacid molecule. As used herein, a “naturally-occurring” nucleic acidmolecule refers to an RNA or DNA molecule having a nucleotide sequencethat occurs in nature (e.g., encodes a natural protein).

[0468] In a second embodiment, a nucleic acid sequence that ishybridizable to the nucleic acid molecule comprising the nucleotidesequence of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25,27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59,or fragments, analogs or derivatives thereof, under conditions ofmoderate stringency is provided. A non-limiting example of moderatestringency hybridization conditions are hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNAat 55° C., followed by one or more washes in 1×SSC, 0.1% SDS at 37° C.Other conditions of moderate stringency that may be used are well-knownwithin the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENTPROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler,1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press,NY.

[0469] In a third embodiment, a nucleic acid that is hybridizable to thenucleic acid molecule comprising the nucleotide sequences SEQ ID NOS: 1,3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39,41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, or fragments, analogs orderivatives thereof, under conditions of low stringency, is provided. Anon-limiting example of low stringency hybridization conditions arehybridization in 35% formamide, 5×SSC, 50 mM Tris-HCl (pH 7.5), 5 mMEDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmonsperm DNA, 10% (wt/vol) dextran sulfate at 40° C., followed by one ormore washes in 2×SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDSat 50° C. Other conditions of low stringency that may be used are wellknown in the art (e.g., as employed for cross-species hybridizations).See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULARBIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER ANDEXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg,1981. Proc Natl Acad Sci USA 78: 6789-6792.

[0470] Conservative Mutations

[0471] In addition to naturally-occurring allelic variants of NOVXsequences that may exist in the population, the skilled artisan willfurther appreciate that changes can be introduced by mutation into thenucleotide sequences SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57,and 59, thereby leading to changes in the amino acid sequences of theencoded NOVX proteins, without altering the functional ability of saidNOVX proteins. For example, nucleotide substitutions leading to aminoacid substitutions at “non-essential” amino acid residues can be made inthe sequence SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60. A“non-essential” amino acid residue is a residue that can be altered fromthe wild-type sequences of the NOVX proteins without altering theirbiological activity, whereas an “essential” amino acid residue isrequired for such biological activity. For example, amino acid residuesthat are conserved among the NOVX proteins of the invention arepredicted to be particularly non-amenable to alteration. Amino acids forwhich conservative substitutions can be made are well-known within theart.

[0472] Another aspect of the invention pertains to nucleic acidmolecules encoding NOVX proteins that contain changes in amino acidresidues that are not essential for activity. Such NOVX proteins differin amino acid sequence from SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54,56, 58, and 60 yet retain biological activity. In one embodiment, theisolated nucleic acid molecule comprises a nucleotide sequence encodinga protein, wherein the protein comprises an amino acid sequence at leastabout 45% homologous to the amino acid sequences SEQ ID NOS: 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44,46, 48, 50, 52, 54, 56, 58, and 60. Preferably, the protein encoded bythe nucleic acid molecule is at least about 60% homologous to SEQ IDNOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36,38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60; more preferably atleast about 70% homologous SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54,56, 58, or 60; still more preferably at least about 80% homologous toSEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60; even morepreferably at least about 90% homologous to SEQ ID NOS: 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46,48, 50, 52, 54, 56, 58, or 60; and most preferably at least about 95%homologous to SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or60.

[0473] An isolated nucleic acid molecule encoding an NOVX proteinhomologous to the protein of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54,56, 58, or 60 can be created by introducing one or more nucleotidesubstitutions, additions or deletions into the nucleotide sequence ofSEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, such thatone or more amino acid substitutions, additions or deletions areintroduced into the encoded protein.

[0474] Mutations can be introduced into SEQ ID NOS: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47,49, 51, 53, 55, 57, and 59 by standard techniques, such as site-directedmutagenesis and PCR-mediated mutagenesis. Preferably, conservative aminoacid substitutions are made at one or more predicted, non-essentialamino acid residues. A “conservative amino acid substitution” is one inwhich the amino acid residue is replaced with an amino acid residuehaving a similar side chain. Families of amino acid residues havingsimilar side chains have been defined within the art. These familiesinclude amino acids with basic side chains (e.g., lysine, arginine,histidine), acidic side chains (e.g., aspartic acid, glutamic acid),uncharged polar side chains (e.g., glycine, asparagine, glutamine,serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g.,alanine, valine, leucine, isoleucine, proline, phenylalanine,methionine, tryptophan), beta-branched side chains (e.g., threonine,valine, isoleucine) and aromatic side chains (e.g., tyrosine,phenylalanine, tryptophan, histidine). Thus, a predicted non-essentialamino acid residue in the NOVX protein is replaced with another aminoacid residue from the same side chain family. Alternatively, in anotherembodiment, mutations can be introduced randomly along all or part of anNOVX coding sequence, such as by saturation mutagenesis, and theresultant mutants can be screened for NOVX biological activity toidentify mutants that retain activity. Following mutagenesis of SEQ IDNOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, the encoded proteincan be expressed by any recombinant technology known in the art and theactivity of the protein can be determined.

[0475] The relatedness of amino acid families may also be determinedbased on side chain interactions. Substituted amino acids may be fullyconserved “strong” residues or fully conserved “weak” residues. The“strong” group of conserved amino acid residues may be any one of thefollowing groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW,wherein the single letter amino acid codes are grouped by those aminoacids that may be substituted for each other. Likewise, the “weak” groupof conserved residues may be any one of the following: CSA, ATV, SAG,STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, VLIM, HFY, wherein the letterswithin each group represent the single letter amino acid code. In oneembodiment, a mutant NOVX protein can be assayed for (i) the ability toform protein:protein interactions with other NOVX proteins, othercell-surface proteins, or biologically-active portions thereof, (ii)complex formation between a mutant NOVX protein and an NOVX ligand; or(iii) the ability of a mutant NOVX protein to bind to an intracellulartarget protein or biologically-active portion thereof, (e.g. avidinproteins).

[0476] In yet another embodiment, a mutant NOVX protein can be assayedfor the ability to regulate a specific biological function (e.g.,regulation of insulin release).

[0477] Antisense Nucleic Acids

[0478] Another aspect of the invention pertains to isolated antisensenucleic acid molecules that are hybridizable to or complementary to thenucleic acid molecule comprising the nucleotide sequence of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37,39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, or fragments, analogs orderivatives thereof. An “antisense” nucleic acid comprises a nucleotidesequence that is complementary to a “sense” nucleic acid encoding aprotein (e.g., complementary to the coding strand of a double-strandedcDNA molecule or complementary to an mRNA sequence). In specificaspects, antisense nucleic acid molecules are provided that comprise asequence complementary to at least about 10, 25, 50, 100, 250 or 500nucleotides or an entire NOVX coding strand, or to only a portionthereof. Nucleic acid molecules encoding fragments, homologs,derivatives and analogs of an NOVX protein of SEQ ID NOS: 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44,46, 48, 50, 52, 54, 56, 58, or 60, or antisense nucleic acidscomplementary to an NOVX nucleic acid sequence of SEQ ID NOS: 1, 3, 5,7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,43, 45, 47, 49, 51, 53, 55, 57, and 59, are additionally provided.

[0479] In one embodiment, an antisense nucleic acid molecule isantisense to a “coding region” of the coding strand of a nucleotidesequence encoding an NOVX protein. The term “coding region” refers tothe region of the nucleotide sequence comprising codons which aretranslated into amino acid residues. In another embodiment, theantisense nucleic acid molecule is antisense to a “noncoding region” ofthe coding strand of a nucleotide sequence encoding the NOVX protein.The term “noncoding region” refers to 5′ and 3′ sequences which flankthe coding region that are not translated into amino acids (i.e., alsoreferred to as 5′ and 3′ untranslated regions).

[0480] Given the coding strand sequences encoding the NOVX proteindisclosed herein, antisense nucleic acids of the invention can bedesigned according to the rules of Watson and Crick or Hoogsteen basepairing. The antisense nucleic acid molecule can be complementary to theentire coding region of NOVX mRNA, but more preferably is anoligonucleotide that is antisense to only a portion of the coding ornoncoding region of NOVX mRNA. For example, the antisenseoligonucleotide can be complementary to the region surrounding thetranslation start site of NOVX mRNA. An antisense oligonucleotide canbe, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50nucleotides in length. An antisense nucleic acid of the invention can beconstructed using chemical synthesis or enzymatic ligation reactionsusing procedures known in the art. For example, an antisense nucleicacid (e.g., an antisense oligonucleotide) can be chemically synthesizedusing naturally-occurring nucleotides or variously modified nucleotidesdesigned to increase the biological stability of the molecules or toincrease the physical stability of the duplex formed between theantisense and sense nucleic acids (e.g., phosphorothioate derivativesand acridine substituted nucleotides can be used).

[0481] Examples of modified nucleotides that can be used to generate theantisense nucleic acid include: 5-fluorouracil, 5-bromouracil,5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine,5-(carboxyhydroxylmethyl) uracil,5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, 3-queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an antisense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest, described further inthe following subsection).

[0482] The antisense nucleic acid molecules of the invention aretypically administered to a subject or generated in situ such that theyhybridize with or bind to cellular mRNA and/or genomic DNA encoding anNOVX protein to thereby inhibit expression of the protein (e.g., byinhibiting transcription and/or translation). The hybridization can beby conventional nucleotide complementarity to form a stable duplex, or,for example, in the case of an antisense nucleic acid molecule thatbinds to DNA duplexes, through specific interactions in the major grooveof the double helix. An example of a route of administration ofantisense nucleic acid molecules of the invention includes directinjection at a tissue site. Alternatively, antisense nucleic acidmolecules can be modified to target selected cells and then administeredsystemically. For example, for systemic administration, antisensemolecules can be modified such that they specifically bind to receptorsor antigens expressed on a selected cell surface (e.g., by linking theantisense nucleic acid molecules to peptides or antibodies that bind tocell surface receptors or antigens). The antisense nucleic acidmolecules can also be delivered to cells using the vectors describedherein. To achieve sufficient nucleic acid molecules, vector constructsin which the antisense nucleic acid molecule is placed under the controlof a strong pol II or pol III promoter are preferred.

[0483] In yet another embodiment, the antisense nucleic acid molecule ofthe invention is an □-anomeric nucleic acid molecule. An □-anomericnucleic acid molecule forms specific double-stranded hybrids withcomplementary RNA in which, contrary to the usual □-units, the strandsrun parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl.Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can alsocomprise a 2′-o-methylribonucleotide (See, e.g., Inoue, et al. 1987.Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See,e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330.

[0484] Ribozymes and PNA Moieties

[0485] Nucleic acid modifications include, by way of non-limitingexample, modified bases, and nucleic acids whose sugar phosphatebackbones are modified or derivatized. These modifications are carriedout at least in part to enhance the chemical stability of the modifiednucleic acid, such that they may be used, for example, as antisensebinding nucleic acids in therapeutic applications in a subject.

[0486] In one embodiment, an antisense nucleic acid of the invention isa ribozyme. Ribozymes are catalytic RNA molecules with ribonucleaseactivity that are capable of cleaving a single-stranded nucleic acid,such as an mRNA, to which they have a complementary region. Thus,ribozymes (e.g., hammerhead ribozymes as described in Haselhoff andGerlach 1988. Nature 334: 585-591) can be used to catalytically cleaveNOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. Aribozyme having specificity for an NOVX-encoding nucleic acid can bedesigned based upon the nucleotide sequence of an NOVX cDNA disclosedherein (i.e., SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25,27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59).For example, a derivative of a Tetrahymena L-19 IVS RNA can beconstructed in which the nucleotide sequence of the active site iscomplementary to the nucleotide sequence to be cleaved in anNOVX-encoding mRNA. See, e.g., U.S. Pat. No. 4,987,071 to Cech, et al.and U.S. Pat. No. 5,116,742 to Cech, et al. NOVX mRNA can also be usedto select a catalytic RNA having a specific ribonuclease activity from apool of RNA molecules. See, e.g., Bartel et al., (1993) Science261:1411-1418.

[0487] Alternatively, NOVX gene expression can be inhibited by targetingnucleotide sequences complementary to the regulatory region of the NOVXnucleic acid (e.g., the NOVX promoter and/or enhancers) to form triplehelical structures that prevent transcription of the NOVX gene in targetcells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene,et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14:807-15.

[0488] In various embodiments, the NOVX nucleic acids can be modified atthe base moiety, sugar moiety or phosphate backbone to improve, e.g.,the stability, hybridization, or solubility of the molecule. Forexample, the deoxyribose phosphate backbone of the nucleic acids can bemodified to generate peptide nucleic acids. See, e.g., Hyrup, et al.,1996. Bioorg Med Chem 4: 5-23. As used herein, the terms “peptidenucleic acids” or “PNAs” refer to nucleic acid mimics (e.g., DNA mimics)in which the deoxyribose phosphate backbone is replaced by apseudopeptide backbone and only the four natural nucleobases areretained. The neutral backbone of PNAs has been shown to allow forspecific hybridization to DNA and RNA under conditions of low ionicstrength. The synthesis of PNA oligomers can be performed using standardsolid phase peptide synthesis protocols as described in Hyrup, et al.,1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93:14670-14675.

[0489] PNAs of NOVX can be used in therapeutic and diagnosticapplications. For example,—PNAs can be used as antisense or antigeneagents for sequence-specific modulation of gene expression by, e.g.,inducing transcription or translation arrest or inhibiting replication.PNAs of NOVX can also be used, for example, in the analysis of singlebase pair mutations in a gene (e.g., PNA directed PCR clamping; asartificial restriction enzymes when used in combination with otherenzymes, e.g., S₁ nucleases (See, Hyrup, et al., 1996.supra); or asprobes or primers for DNA sequence and hybridization (See, Hyrup, etal., 1996, supra; Perry-O'Keefe, et al., 1996. supra).

[0490] In another embodiment, PNAs of NOVX can be modified, e.g., toenhance their stability or cellular uptake, by attaching lipophilic orother helper groups to PNA, by the formation of PNA-DNA chimeras, or bythe use of liposomes or other techniques of drug delivery known in theart. For example, PNA-DNA chimeras of NOVX can be generated that maycombine the advantageous properties of PNA and DNA. Such chimeras allowDNA recognition enzymes (e.g., RNase H and DNA polymerases) to interactwith the DNA portion while the PNA portion would provide high bindingaffinity and specificity. PNA-DNA chimeras can be linked using linkersof appropriate lengths selected in terms of base stacking, number ofbonds between the nucleobases, and orientation (see, Hyrup, et al.,1996. supra). The synthesis of PNA-DNA chimeras can be performed asdescribed in Hyrup, et al., 1996. supra and Finn, et al., 1996. NuclAcids Res 24: 3357-3363. For example, a DNA chain can be synthesized ona solid support using standard phosphoramidite coupling chemistry, andmodified nucleoside analogs, e.g.,5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can beused between the PNA and the 5′ end of DNA. See, e.g., Mag, et al.,1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in astepwise manner to produce a chimeric molecule with a 5′ PNA segment anda 3′ DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively,chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNAsegment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5:1119-11124.

[0491] In other embodiments, the oligonucleotide may include otherappended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. SciU.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci 84:648-652; PCT Publication No. WO88/09810) or the blood-brain barrier(see, e.g., PCT Publication No. WO 89/10134). In addition,oligonucleotides can be modified with hybridization triggered cleavageagents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) orintercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). Tothis end, the oligonucleotide may be conjugated to another molecule,e.g., a peptide, a hybridization triggered cross-linking agent, atransport agent, a hybridization-triggered cleavage agent, and the like.

[0492] NOVX Polypeptides

[0493] A polypeptide according to the invention includes a polypeptideincluding the amino acid sequence of NOVX polypeptides whose sequencesare provided in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or60. The invention also includes a mutant or variant protein any of whoseresidues may be changed from the corresponding residues shown in SEQ IDNOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36,38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 while still encoding aprotein that maintains its NOVX activities and physiological functions,or a functional fragment thereof.

[0494] In general, an NOVX variant that preserves NOVX-like functionincludes any variant in which residues at a particular position in thesequence have been substituted by other amino acids, and further includethe possibility of inserting an additional residue or residues betweentwo residues of the parent protein as well as the possibility ofdeleting one or more residues from the parent sequence. Any amino acidsubstitution, insertion, or deletion is encompassed by the invention. Infavorable circumstances, the substitution is a conservative substitutionas defined above.

[0495] One aspect of the invention pertains to isolated NOVX proteins,and biologically-active portions thereof, or derivatives, fragments,analogs or homologs thereof. Also provided are polypeptide fragmentssuitable for use as immunogens to raise anti-NOVX antibodies. In oneembodiment, native NOVX proteins can be isolated from cells or tissuesources by an appropriate purification scheme using standard proteinpurification techniques. In another embodiment, NOVX proteins areproduced by recombinant DNA techniques. Alternative to recombinantexpression, an NOVX protein or polypeptide can be synthesized chemicallyusing standard peptide synthesis techniques.

[0496] An “isolated” or “purified” polypeptide or protein orbiologically-active portion thereof is substantially free of cellularmaterial or other contaminating proteins from the cell or tissue sourcefrom which the NOVX protein is derived, or substantially free fromchemical precursors or other chemicals when chemically synthesized. Thelanguage “substantially free of cellular material” includes preparationsof NOVX proteins in which the protein is separated from cellularcomponents of the cells from which it is isolated orrecombinantly-produced. In one embodiment, the language “substantiallyfree of cellular material” includes preparations of NOVX proteins havingless than about 30% (by dry weight) of non-NOVX proteins (also referredto herein as a “contaminating protein”), more preferably less than about20% of non-NOVX proteins, still more preferably less than about 10% ofnon-NOVX proteins, and most preferably less than about 5% of non-NOVXproteins. When the NOVX protein or biologically-active portion thereofis recombinantly-produced, it is also preferably substantially free ofculture medium, i.e., culture medium represents less than about 20%,more preferably less than about 10%, and most preferably less than about5% of the volume of the NOVX protein preparation.

[0497] The language “substantially free of chemical precursors or otherchemicals” includes preparations of NOVX proteins in which the proteinis separated from chemical precursors or other chemicals that areinvolved in the synthesis of the protein. In one embodiment, thelanguage “substantially free of chemical precursors or other chemicals”includes preparations of NOVX proteins having less than about 30% (bydry weight) of chemical precursors or non-NOVX chemicals, morepreferably less than about 20% chemical precursors or non-NOVXchemicals, still more preferably less than about 10% chemical precursorsor non-NOVX chemicals, and most preferably less than about 5% chemicalprecursors or non-NOVX chemicals.

[0498] Biologically-active portions of NOVX proteins include peptidescomprising amino acid sequences sufficiently homologous to or derivedfrom the amino acid sequences of the NOVX proteins (e.g., the amino acidsequence shown in SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58,or 60) that include fewer amino acids than the full-length NOVXproteins, and exhibit at least one activity of an NOVX protein.Typically, biologically-active portions comprise a domain or motif withat least one activity of the NOVX protein. A biologically-active portionof an NOVX protein can be a polypeptide which is, for example, 10, 25,50, 100 or more amino acid residues in length.

[0499] Moreover, other biologically-active portions, in which otherregions of the protein are deleted, can be prepared by recombinanttechniques and evaluated for one or more of the functional activities ofa native NOVX protein.

[0500] In an embodiment, the NOVX protein has an amino acid sequenceshown SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28,30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60. Inother embodiments, the NOVX protein is substantially homologous to SEQID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60, and retains thefunctional activity of the protein of SEQ ID NOS: 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48,50, 52, 54, 56, 58, or 60, yet differs in amino acid sequence due tonatural allelic variation or mutagenesis, as described in detail, below.

[0501] Accordingly, in another embodiment, the NOVX protein is a proteinthat comprises an amino acid sequence at least about 45% homologous tothe amino acid sequence SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56,58, or 60, and retains the functional activity of the NOVX proteins ofSEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60.

[0502] Determining Homology Between Two or More Sequences

[0503] To determine the percent homology of two amino acid sequences orof two nucleic acids, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in the sequence of a first aminoacid or nucleic acid sequence for optimal alignment with a second aminoor nucleic acid sequence). The amino acid residues or nucleotides atcorresponding amino acid positions or nucleotide positions are thencompared. When a position in the first sequence is occupied by the sameamino acid residue or nucleotide as the corresponding position in thesecond sequence, then the molecules are homologous at that position(i.e., as used herein amino acid or nucleic acid “homology” isequivalent to amino acid or nucleic acid “identity”).

[0504] The nucleic acid sequence homology may be determined as thedegree of identity between two sequences. The homology may be determinedusing computer programs known in the art, such as GAP software providedin the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol48: 443-453. Using GCG GAP software with the following settings fornucleic acid sequence comparison: GAP creation penalty of 5.0 and GAPextension penalty of 0.3, the coding region of the analogous nucleicacid sequences referred to above exhibits a degree of identitypreferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, withthe CDS (encoding) part of the DNA sequence shown in SEQ ID NOS: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,43, 45, 47, 49, 51, 53, 55, 57, and 59.

[0505] The term “sequence identity” refers to the degree to which twopolynucleotide or polypeptide sequences are identical on aresidue-by-residue basis over a particular region of comparison. Theterm “percentage of sequence identity” is calculated by comparing twooptimally aligned sequences over that region of comparison, determiningthe number of positions at which the identical nucleic acid base (e.g.,A, T, C, G, U, or I, in the case of nucleic acids) occurs in bothsequences to yield the number of matched positions, dividing the numberof matched positions by the total number of positions in the region ofcomparison (i.e., the window size), and multiplying the result by 100 toyield the percentage of sequence identity. The term “substantialidentity” as used herein denotes a characteristic of a polynucleotidesequence, wherein the polynucleotide comprises a sequence that has atleast 80 percent sequence identity, preferably at least 85 percentidentity and often 90 to 95 percent sequence identity, more usually atleast 99 percent sequence identity as compared to a reference sequenceover a comparison region.

[0506] Chimeric and Fusion Proteins

[0507] The invention also provides NOVX chimeric or fusion proteins. Asused herein, an NOVX “chimeric protein” or “fusion protein” comprises anNOVX polypeptide operatively-linked to a non-NOVX polypeptide. An “NOVXpolypeptide” refers to a polypeptide having an amino acid sequencecorresponding to an NOVX protein SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52,54, 56, 58, or 60), whereas a “non-NOVX polypeptide” refers to apolypeptide having an amino acid sequence corresponding to a proteinthat is not substantially homologous to the NOVX protein, e.g., aprotein that is different from the NOVX protein and that is derived fromthe same or a different organism. Within an NOVX fusion protein the NOVXpolypeptide can correspond to all or a portion of an NOVX protein. Inone embodiment, an NOVX fusion protein comprises at least onebiologically-active portion of an NOVX protein. In another embodiment,an NOVX fusion protein comprises at least two biologically-activeportions of an NOVX protein. In yet another embodiment, an NOVX fusionprotein comprises at least three biologically-active portions of an NOVXprotein. Within the fusion protein, the term “operatively-linked” isintended to indicate that the NOVX polypeptide and the non-NOVXpolypeptide are fused in-frame with one another. The non-NOVXpolypeptide can be fused to the N-terminus or C-terminus of the NOVXpolypeptide.

[0508] In one embodiment, the fusion protein is a GST-NOVX fusionprotein in which the NOVX sequences are fused to the C-terminus of theGST (glutathione S-transferase) sequences. Such fusion proteins canfacilitate the purification of recombinant NOVX polypeptides.

[0509] In another embodiment, the fusion protein is an NOVX proteincontaining a heterologous signal sequence at its N-terminus. In certainhost cells (e.g., mammalian host cells), expression and/or secretion ofNOVX can be increased through use of a heterologous signal sequence.

[0510] In yet another embodiment, the fusion protein is anNOVX-immunoglobulin fusion protein in which the NOVX sequences are fusedto sequences derived from a member of the immunoglobulin protein family.The NOVX-immunoglobulin fusion proteins of the invention can beincorporated into pharmaceutical compositions and administered to asubject to inhibit an interaction between an NOVX ligand and an NOVXprotein on the surface of a cell, to thereby suppress NOVX-mediatedsignal transduction in vivo. The NOVX-immunoglobulin fusion proteins canbe used to affect the bioavailability of an NOVX cognate ligand.Inhibition of the NOVX ligand/NOVX interaction may be usefultherapeutically for both the treatment of proliferative anddifferentiative disorders, as well as modulating (e.g. promoting orinhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusionproteins of the invention can be used as immunogens to produce anti-NOVXantibodies in a subject, to purify NOVX ligands, and in screening assaysto identify molecules that inhibit the interaction of NOVX with an NOVXligand.

[0511] An NOVX chimeric or fusion protein of the invention can beproduced by standard recombinant DNA techniques. For example, DNAfragments coding for the different polypeptide sequences are ligatedtogether in-frame in accordance with conventional techniques, e.g., byemploying blunt-ended or stagger-ended termini for ligation, restrictionenzyme digestion to provide for appropriate termini, filling-in ofcohesive ends as appropriate, alkaline phosphatase treatment to avoidundesirable joining, and enzymatic ligation. In another embodiment, thefusion gene can be synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers that give rise tocomplementary overhangs between two consecutive gene fragments that cansubsequently be annealed and reamplified to generate a chimeric genesequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS INMOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expressionvectors are commercially available that already encode a fusion moiety(e.g., a GST polypeptide). An NOVX-encoding nucleic acid can be clonedinto such an expression vector such that the fusion moiety is linkedin-frame to the NOVX protein.

[0512] NOVX Agonists and Antagonists

[0513] The invention also pertains to variants of the NOVX proteins thatfunction as either NOVX agonists (i.e., mimetics) or as NOVXantagonists. Variants of the NOVX protein can be generated bymutagenesis (e.g., discrete point mutation or truncation of the NOVXprotein). An agonist of the NOVX protein can retain substantially thesame, or a subset of, the biological activities of the naturallyoccurring form of the NOVX protein. An antagonist of the NOVX proteincan inhibit one or more of the activities of the naturally occurringform of the NOVX protein by, for example, competitively binding to adownstream or upstream member of a cellular signaling cascade whichincludes the NOVX protein. Thus, specific biological effects can beelicited by treatment with a variant of limited function. In oneembodiment, treatment of a subject with a variant having a subset of thebiological activities of the naturally occurring form of the protein hasfewer side effects in a subject relative to treatment with the naturallyoccurring form of the NOVX proteins.

[0514] Variants of the NOVX proteins that function as either NOVXagonists (i.e., mimetics) or as NOVX antagonists can be identified byscreening combinatorial libraries of mutants (e.g., truncation mutants)of the NOVX proteins for NOVX protein agonist or antagonist activity. Inone embodiment, a variegated library of NOVX variants is generated bycombinatorial mutagenesis at the nucleic acid level and is encoded by avariegated gene library. A variegated library of NOVX variants can beproduced by, for example, enzymatically ligating a mixture of syntheticoligonucleotides into gene sequences such that a degenerate set ofpotential NOVX sequences is expressible as individual polypeptides, oralternatively, as a set of larger fusion proteins (e.g., for phagedisplay) containing the set of NOVX sequences therein. There are avariety of methods which can be used to produce libraries of potentialNOVX variants from a degenerate oligonucleotide sequence. Chemicalsynthesis of a degenerate gene sequence can be performed in an automaticDNA synthesizer, and the synthetic gene then ligated into an appropriateexpression vector. Use of a degenerate set of genes allows for theprovision, in one mixture, of all of the sequences encoding the desiredset of potential NOVX sequences. Methods for synthesizing degenerateoligonucleotides are well-known within the art. See, e.g., Narang, 1983.Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323;Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. AcidsRes. 11: 477.

[0515] Polypeptide Libraries

[0516] In addition, libraries of fragments of the NOVX protein codingsequences can be used to generate a variegated population of NOVXfragments for screening and subsequent selection of variants of an NOVXprotein. In one embodiment, a library of coding sequence fragments canbe generated by treating a double stranded PCR fragment of an NOVXcoding sequence with a nuclease under conditions wherein nicking occursonly about once per molecule, denaturing the double stranded DNA,renaturing the DNA to form double-stranded DNA that can includesense/antisense pairs from different nicked products, removing singlestranded portions from reformed duplexes by treatment with S, nuclease,and ligating the resulting fragment library into an expression vector.By this method, expression libraries can be derived which encodesN-terminal and internal fragments of various sizes of the NOVX proteins.

[0517] Various techniques are known in the art for screening geneproducts of combinatorial libraries made by point mutations ortruncation, and for screening cDNA libraries for gene products having aselected property. Such techniques are adaptable for rapid screening ofthe gene libraries generated by the combinatorial mutagenesis of NOVXproteins. The most widely used techniques, which are amenable to highthroughput analysis, for screening large gene libraries typicallyinclude cloning the gene library into replicable expression vectors,transforming appropriate cells with the resulting library of vectors,and expressing the combinatorial genes under conditions in whichdetection of a desired activity facilitates isolation of the vectorencoding the gene whose product was detected. Recursive ensemblemutagenesis (REM), a new technique that enhances the frequency offunctional mutants in the libraries, can be used in combination with thescreening assays to identify NOVX variants. See, e.g., Arkin andYourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, etal., 1993. Protein Engineering 6:327-331.

[0518] Anti-NOVX Antibodies

[0519] Also included in the invention are antibodies to NOVX proteins,or fragments of NOVX proteins. The term “antibody” as used herein refersto immunoglobulin molecules and immunologically active portions ofimmunoglobulin (Ig) molecules, i.e., molecules that contain an antigenbinding site that specifically binds (immunoreacts with) an antigen.Such antibodies include, but are not limited to, polyclonal, monoclonal,chimeric, single chain, F_(ab), F_(ab′) and F_((ab′)2) fragments, and anF_(ab) expression library. In general, an antibody molecule obtainedfrom humans relates to any of the classes IgG, IgM, IgA, IgE and IgD,which differ from one another by the nature of the heavy chain presentin the molecule. Certain classes have subclasses as well, such as IgG₁,IgG₂, and others. Furthermore, in humans, the light chain may be a kappachain or a lambda chain. Reference herein to antibodies includes areference to all such classes, subclasses and types of human antibodyspecies.

[0520] An isolated NOVX-related protein of the invention may be intendedto serve as an antigen, or a portion or fragment thereof, andadditionally can be used as an immunogen to generate antibodies thatimmunospecifically bind the antigen, using standard techniques forpolyclonal and monoclonal antibody preparation. The full-length proteincan be used or, alternatively, the invention provides antigenic peptidefragments of the antigen for use as immunogens. An antigenic peptidefragment comprises at least 6 amino acid residues of the amino acidsequence of the full length protein and encompasses an epitope thereofsuch that an antibody raised against the peptide forms a specific immunecomplex with the full length protein or with any fragment that containsthe epitope. Preferably, the antigenic peptide comprises at least 10amino acid residues, or at least 15 amino acid residues, or at least 20amino acid residues, or at least 30 amino acid residues. Preferredepitopes encompassed by the antigenic peptide are regions of the proteinthat are located on its surface; commonly these are hydrophilic regions.

[0521] In certain embodiments of the invention, at least one epitopeencompassed by the antigenic peptide is a region of NOVX-related proteinthat is located on the surface of the protein, e.g., a hydrophilicregion. A hydrophobicity analysis of the human NOVX-related proteinsequence will indicate which regions of a NOVX-related protein areparticularly hydrophilic and, therefore, are likely to encode surfaceresidues useful for targeting antibody production. As a means fortargeting antibody production, hydropathy plots showing regions ofhydrophilicity and hydrophobicity may be generated by any method wellknown in the art, including, for example, the Kyte Doolittle or the HoppWoods methods, either with or without Fourier transformation. See, e.g.,Hopp and Woods, 1981, Proc. Nat. Acad. Sc. USA 78: 3824-3828; Kyte andDoolittle 1982, J. Mol. Biol. 157: 105-142, each of which isincorporated herein by reference in its entirety. Antibodies that arespecific for one or more domains within an antigenic protein, orderivatives, fragments, analogs or homologs thereof, are also providedherein.

[0522] A protein of the invention, or a derivative, fragment, analog,homolog or ortholog thereof, may be utilized as an immunogen in thegeneration of antibodies that immunospecifically bind these proteincomponents.

[0523] Various procedures known within the art may be used for theproduction of polyclonal or monoclonal antibodies directed against aprotein of the invention, or against derivatives, fragments, analogshomologs or orthologs thereof (see, for example, Antibodies: ALaboratory Manual, Harlow and Lane, 1988, Cold Spring Harbor LaboratoryPress, Cold Spring Harbor, N.Y., incorporated herein by reference). Someof these antibodies are discussed below.

[0524] Polyclonal Antibodies

[0525] For the production of polyclonal antibodies, various suitablehost animals (e.g., rabbit, goat, mouse or other mammal) may beimmunized by one or more injections with the native protein, a syntheticvariant thereof, or a derivative of the foregoing. An appropriateimmunogenic preparation can contain, for example, the naturallyoccurring immunogenic protein, a chemically synthesized polypeptiderepresenting the immunogenic protein, or a recombinantly expressedimmunogenic protein. Furthermore, the protein may be conjugated to asecond protein known to be immunogenic in the mammal being immunized.Examples of such immunogenic proteins include but are not limited tokeyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, andsoybean trypsin inhibitor. The preparation can further include anadjuvant. Various adjuvants used to increase the immunological responseinclude, but are not limited to, Freund's (complete and incomplete),mineral gels (e.g., aluminum hydroxide), surface active substances(e.g., lysolecithin, pluronic polyols, polyanions, peptides, oilemulsions, dinitrophenol, etc.), adjuvants usable in humans such asBacille Calmette-Guerin and Corynebacterium parvum, or similarimmunostimulatory agents. Additional examples of adjuvants which can beemployed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetictrehalose dicorynomycolate).

[0526] The polyclonal antibody molecules directed against theimmunogenic protein can be isolated from the mammal (e.g., from theblood) and further purified by well known techniques, such as affinitychromatography using protein A or protein G, which provide primarily theIgG fraction of immune serum. Subsequently, or alternatively, thespecific antigen which is the target of the immunoglobulin sought, or anepitope thereof, may be immobilized on a column to purify the immunespecific antibody by immunoaffinity chromatography. Purification ofimmunoglobulins is discussed, for example, by D. Wilkinson (TheScientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14,No. 8 (Apr. 17, 2000), pp. 25-28).

[0527] Monoclonal Antibodies

[0528] The term “monoclonal antibody” (MAb) or “monoclonal antibodycomposition”, as used herein, refers to a population of antibodymolecules that contain only one molecular species of antibody moleculeconsisting of a unique light chain gene product and a unique heavy chaingene product. In particular, the complementarity determining regions(CDRs) of the monoclonal antibody are identical in all the molecules ofthe population. MAbs thus contain an antigen binding site capable ofimmunoreacting with a particular epitope of the antigen characterized bya unique binding affinity for it.

[0529] Monoclonal antibodies can be prepared using hybridoma methods,such as those described by Kohler and Milstein, Nature, 256:495 (1975).In a hybridoma method, a mouse, hamster, or other appropriate hostanimal, is typically immunized with an immunizing agent to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the immunizing agent. Alternatively, thelymphocytes can be immunized in vitro.

[0530] The immunizing agent will typically include the protein antigen,a fragment thereof or a fusion protein thereof. Generally, eitherperipheral blood lymphocytes are used if cells of human origin aredesired, or spleen cells or lymph node cells are used if non-humanmammalian sources are desired. The lymphocytes are then fused with animmortalized cell line using a suitable fusing agent, such aspolyethylene glycol, to form a hybridoma cell (Goding, MONOCLONALANTIBODIES: PRINCIPLES AND PRACTICE, Academic Press, (1986) pp. 59-103).Immortalized cell lines are usually transformed mammalian cells,particularly myeloma cells of rodent, bovine and human origin. Usually,rat or mouse myeloma cell lines are employed. The hybridoma cells can becultured in a suitable culture medium that preferably contains one ormore substances that inhibit the growth or survival of the unfused,immortalized cells. For example, if the parental cells lack the enzymehypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), theculture medium for the hybridomas typically will include hypoxanthine,aminopterin, and thymidine (“HAT medium”), which substances prevent thegrowth of HGPRT-deficient cells.

[0531] Preferred immortalized cell lines are those that fuseefficiently, support stable high level expression of antibody by theselected antibody-producing cells, and are sensitive to a medium such asHAT medium. More preferred immortalized cell lines are murine myelomalines, which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur etal., MONOCLONAL ANTIBODY PRODUCTION TECHNIQUES AND APPLICATIONS, MarcelDekker, Inc., New York, (1987) pp. 51-63).

[0532] The culture medium in which the hybridoma cells are cultured canthen be assayed for the presence of monoclonal antibodies directedagainst the antigen. Preferably, the binding specificity of monoclonalantibodies produced by the hybridoma cells is determined byimmunoprecipitation or by an in vitro binding assay, such asradioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).Such techniques and assays are known in the art. The binding affinity ofthe monoclonal antibody can, for example, be determined by the Scatchardanalysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).Preferably, antibodies having a high degree of specificity and a highbinding affinity for the target antigen are isolated.

[0533] After the desired hybridoma cells are identified, the clones canbe subcloned by limiting dilution procedures and grown by standardmethods. Suitable culture media for this purpose include, for example,Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively,the hybridoma cells can be grown in vivo as ascites in a mammal. Themonoclonal antibodies secreted by the subclones can be isolated orpurified from the culture medium or ascites fluid by conventionalimmunoglobulin purification procedures such as, for example, proteinA-Sepharose, hydroxylapatite chromatography, gel electrophoresis,dialysis, or affinity chromatography.

[0534] The monoclonal antibodies can also be made by recombinant DNAmethods, such as those described in U.S. Pat. No. 4,816,567. DNAencoding the monoclonal antibodies of the invention can be readilyisolated and sequenced using conventional procedures (e.g., by usingoligonucleotide probes that are capable of binding specifically to genesencoding the heavy and light chains of murine antibodies). The hybridomacells of the invention serve as a preferred source of such DNA. Onceisolated, the DNA can be placed into expression vectors, which are thentransfected into host cells such as simian COS cells, Chinese hamsterovary (CHO) cells, or myeloma cells that do not otherwise produceimmunoglobulin protein, to obtain the synthesis of monoclonal antibodiesin the recombinant host cells. The DNA also can be modified, forexample, by substituting the coding sequence for human heavy and lightchain constant domains in place of the homologous murine sequences (U.S.Pat. No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or bycovalently joining to the immunoglobulin coding sequence all or part ofthe coding sequence for a non-immunoglobulin polypeptide. Such anon-immunoglobulin polypeptide can be substituted for the constantdomains of an antibody of the invention, or can be substituted for thevariable domains of one antigen-combining site of an antibody of theinvention to create a chimeric bivalent antibody.

[0535] Humanized Antibodies

[0536] The antibodies directed against the protein antigens of theinvention can further comprise humanized antibodies or human antibodies.These antibodies are suitable for administration to humans withoutengendering an immune response by the human against the administeredimmunoglobulin. Humanized forms of antibodies are chimericimmunoglobulins, immunoglobulin chains or fragments thereof (such as Fv,Fab, Fab′, F(ab′)₂ or other antigen-binding subsequences of antibodies)that are principally comprised of the sequence of a humanimmunoglobulin, and contain minimal sequence derived from a non-humanimmunoglobulin. Humanization can be performed following the method ofWinter and co-workers (Jones et al., Nature, 321:522-525 (1986);Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science,239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences forthe corresponding sequences of a human antibody. (See also U.S. Pat. No.5,225,539.) In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies can also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of theframework regions are those of a human immunoglobulin consensussequence. The humanized antibody optimally also will comprise at least aportion of an immunoglobulin constant region (Fc), typically that of ahuman immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; andPresta, Curr. Op. Struct. Biol., 2:593-596 (1992)).

[0537] Human Antibodies

[0538] Fully human antibodies relate to antibody molecules in whichessentially the entire sequences of both the light chain and the heavychain, including the CDRs, arise from human genes. Such antibodies aretermed “human antibodies”, or “fully human antibodies” herein. Humanmonoclonal antibodies can be prepared by the trioma technique; the humanB-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4:72) and the EBV hybridoma technique to produce human monoclonalantibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCERTHERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies maybe utilized in the practice of the present invention and may be producedby using human hybridomas (see Cote, et al., 1983. Proc Natl Acad SciUSA 80: 2026-2030) or by transforming human B-cells with Epstein BarrVirus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES ANDCANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

[0539] In addition, human antibodies can also be produced usingadditional techniques, including phage display libraries (Hoogenboom andWinter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.,222:581 (1991)). Similarly, human antibodies can be made by introducinghuman immunoglobulin loci into transgenic animals, e.g., mice in whichthe endogenous immunoglobulin genes have been partially or completelyinactivated. Upon challenge, human antibody production is observed,which closely resembles that seen in humans in all respects, includinggene rearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al.(Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859(1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al,(NatureBiotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14,826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93(1995)).

[0540] Human antibodies may additionally be produced using transgenicnonhuman animals which are modified so as to produce fully humanantibodies rather than the animal's endogenous antibodies in response tochallenge by an antigen. (See PCT publication WO94/02602). Theendogenous genes encoding the heavy and light immunoglobulin chains inthe nonhuman host have been incapacitated, and active loci encodinghuman heavy and light chain immunoglobulins are inserted into the host'sgenome. The human genes are incorporated, for example, using yeastartificial chromosomes containing the requisite human DNA segments. Ananimal which provides all the desired modifications is then obtained asprogeny by crossbreeding intermediate transgenic animals containingfewer than the full complement of the modifications. The preferredembodiment of such a nonhuman animal is a mouse, and is termed theXenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096.This animal produces B cells which secrete fully human immunoglobulins.The antibodies can be obtained directly from the animal afterimmunization with an immunogen of interest, as, for example, apreparation of a polyclonal antibody, or alternatively from immortalizedB cells derived from the animal, such as hybridomas producing monoclonalantibodies. Additionally, the genes encoding the immunoglobulins withhuman variable regions can be recovered and expressed to obtain theantibodies directly, or can be further modified to obtain analogs ofantibodies such as, for example, single chain Fv molecules.

[0541] An example of a method of producing a nonhuman host, exemplifiedas a mouse, lacking expression of an endogenous immunoglobulin heavychain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by amethod including deleting the J segment genes from at least oneendogenous heavy chain locus in an embryonic stem cell to preventrearrangement of the locus and to prevent formation of a transcript of arearranged immunoglobulin heavy chain locus, the deletion being effectedby a targeting vector containing a gene encoding a selectable marker;and producing from the embryonic stem cell a transgenic mouse whosesomatic and germ cells contain the gene encoding the selectable marker.

[0542] A method for producing an antibody of interest, such as a humanantibody, is disclosed in U.S. Pat. No. 5,916,771. It includesintroducing an expression vector that contains a nucleotide sequenceencoding a heavy chain into one mammalian host cell in culture,introducing an expression vector containing a nucleotide sequenceencoding a light chain into another mammalian host cell, and fusing thetwo cells to form a hybrid cell. The hybrid cell expresses an antibodycontaining the heavy chain and the light chain.

[0543] In a further improvement on this procedure, a method foridentifying a clinically relevant epitope on an immunogen, and acorrelative method for selecting an antibody that bindsimmunospecifically to the relevant epitope with high affinity, aredisclosed in PCT publication WO 99/53049.

[0544] F_(ab) Fragments and Single Chain Antibodies

[0545] According to the invention, techniques can be adapted for theproduction of single-chain antibodies specific to an antigenic proteinof the invention (see e.g., U.S. Pat. No. 4,946,778). In addition,methods can be adapted for the construction of F_(ab) expressionlibraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allowrapid and effective identification of monoclonal F_(ab) fragments withthe desired specificity for a protein or derivatives, fragments, analogsor homologs thereof. Antibody fragments that contain the idiotypes to aprotein antigen may be produced by techniques known in the artincluding, but not limited to: (i) an F_((ab)2) fragment produced bypepsin digestion of an antibody molecule; (ii) an Fab fragment generatedby reducing the disulfide bridges of an F_((ab)2) fragment; (iii) anF_(ab) fragment generated by the treatment of the antibody molecule withpapain and a reducing agent and (iv) F_(v) fragments.

[0546] Bispecific Antibodies

[0547] Bispecific antibodies are monoclonal, preferably human orhumanized, antibodies that have binding specificities for at least twodifferent antigens. In the present case, one of the bindingspecificities is for an antigenic protein of the invention. The secondbinding target is any other antigen, and advantageously is acell-surface protein or receptor or receptor subunit. Methods for makingbispecific antibodies are known in the art. Traditionally, therecombinant production of bispecific antibodies is based on theco-expression of two immunoglobulin heavy-chain/light-chain pairs, wherethe two heavy chains have different specificities (Milstein and Cuello,Nature, 305:537-539 (1983)). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of ten different antibody molecules, ofwhich only one has the correct bispecific structure. The purification ofthe correct molecule is usually accomplished by affinity chromatographysteps. Similar procedures are disclosed in WO 93/08829, published May13, 1993, and in Traunecker et al., 1991 EMBO J., 10:3655-3659.

[0548] Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have the firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology, 121:210 (1986).

[0549] According to another approach described in WO 96/27011, theinterface between a pair of antibody molecules can be engineered tomaximize the percentage of heterodimers which are recovered fromrecombinant cell culture. The preferred interface comprises at least apart of the CH3 region of an antibody constant domain. In this method,one or more small amino acid side chains from the interface of the firstantibody molecule are replaced with larger side chains (e.g. tyrosine ortryptophan). Compensatory “cavities” of identical or similar size to thelarge side chain(s) are created on the interface of the second antibodymolecule by replacing large amino acid side chains with smaller ones(e.g. alanine or threonine). This provides a mechanism for increasingthe yield of the heterodimer over other unwanted end-products such ashomodimers.

[0550] Bispecific antibodies can be prepared as full length antibodiesor antibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniquesfor generating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared using chemical linkage. Brennan et al., Science 229:81 (1985)describe a procedure wherein intact antibodies are proteolyticallycleaved to generate F(ab′)₂ fragments. These fragments are reduced inthe presence of the dithiol complexing agent sodium arsenite tostabilize vicinal dithiols and prevent intermolecular disulfideformation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

[0551] Additionally, Fab′ fragments can be directly recovered from E.coli and chemically coupled to form bispecific antibodies. Shalaby etal., J. Exp. Med. 175:217-225 (1992) describe the production of a fullyhumanized bispecific antibody F(ab′)₂ molecule. Each Fab′ fragment wasseparately secreted from E. coli and subjected to directed chemicalcoupling in vitro to form the bispecific antibody. The bispecificantibody thus formed was able to bind to cells overexpressing the ErbB2receptor and normal human T cells, as well as trigger the lytic activityof human cytotoxic lymphocytes against human breast tumor targets.

[0552] Various techniques for making and isolating bispecific antibodyfragments directly from recombinant cell culture have also beendescribed. For example, bispecific antibodies have been produced usingleucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992).The leucine zipper peptides from the Fos and Jun proteins were linked tothe Fab′ portions of two different antibodies by gene fusion. Theantibody homodimers were reduced at the hinge region to form monomersand then re-oxidized to form the antibody heterodimers. This method canalso be utilized for the production of antibody homodimers. The“diabody” technology described by Hollinger et al., Proc. Natl. Acad.Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism formaking bispecific antibody fragments. The fragments comprise aheavy-chain variable domain (V_(H)) connected to a light-chain variabledomain (V_(L)) by a linker which is too short to allow pairing betweenthe two domains on the same chain. Accordingly, the V_(H) and V_(L)domains of one fragment are forced to pair with the complementary V_(L)and V_(H) domains of another fragment, thereby forming twoantigen-binding sites. Another strategy for making bispecific antibodyfragments by the use of single-chain Fv (sFv) dimers has also beenreported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodieswith more than two valencies are contemplated. For example, trispecificantibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0553] Exemplary bispecific antibodies can bind to two differentepitopes, at least one of which originates in the protein antigen of theinvention. Alternatively, an anti-antigenic arm of an immunoglobulinmolecule can be combined with an arm which binds to a triggeringmolecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2,CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64),FcγRII (CD32) and FcγRIII (CD16) so as to focus cellular defensemechanisms to the cell expressing the particular antigen. Bispecificantibodies can also be used to direct cytotoxic agents to cells whichexpress a particular antigen. These antibodies possess anantigen-binding arm and an arm which binds a cytotoxic agent or aradionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Anotherbispecific antibody of interest binds the protein antigen describedherein and further binds tissue factor (TF).

[0554] Heteroconjugate Antibodies

[0555] Heteroconjugate antibodies are also within the scope of thepresent invention. Heteroconjugate antibodies are composed of twocovalently joined antibodies. Such antibodies have, for example, beenproposed to target immune system cells to unwanted cells (U.S. Pat. No.4,676,980), and for treatment of HIV infection (WO 91/00360; WO92/200373; EP 03089). It is contemplated that the antibodies can beprepared in vitro using known methods in synthetic protein chemistry,including those involving crosslinking agents. For example, immunotoxinscan be constructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

[0556] Effector Function Engineering

[0557] It can be desirable to modify the antibody of the invention withrespect to effector function, so as to enhance, e.g., the effectivenessof the antibody in treating cancer. For example, cysteine residue(s) canbe introduced into the Fc region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedcan have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195(1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimericantibodies with enhanced anti-tumor activity can also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53: 2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and can thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design, 3: 219-230 (1989).

[0558] Immunoconjugates

[0559] The invention also pertains to immunoconjugates comprising anantibody conjugated to a cytotoxic agent such as a chemotherapeuticagent, toxin (e.g., an enzymatically active toxin of bacterial, fungal,plant, or animal origin, or fragments thereof), or a radioactive isotope(i.e., a radioconjugate).

[0560] Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y,and ¹⁸⁶Re.

[0561] Conjugates of the antibody and cytotoxic agent are made using avariety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026.

[0562] In another embodiment, the antibody can be conjugated to a“receptor” (such streptavidin) for utilization in tumor pretargetingwherein the antibody-receptor conjugate is administered to the patient,followed by removal of unbound conjugate from the circulation using aclearing agent and then administration of a “ligand” (e.g., avidin) thatis in turn conjugated to a cytotoxic agent.

[0563] In one embodiment, methods for the screening of antibodies thatpossess the desired specificity include, but are not limited to,enzyme-linked immunosorbent assay (ELISA) and otherimmunologically-mediated techniques known within the art. In a specificembodiment, selection of antibodies that are specific to a particulardomain of an NOVX protein is facilitated by generation of hybridomasthat bind to the fragment of an NOVX protein possessing such a domain.Thus, antibodies that are specific for a desired domain within an NOVXprotein, or derivatives, fragments, analogs or homologs thereof, arealso provided herein.

[0564] Anti-NOVX antibodies may be used in methods known within the artrelating to the localization and/or quantitation of an NOVX protein(e.g., for use in measuring levels of the NOVX protein withinappropriate physiological samples, for use in diagnostic methods, foruse in imaging the protein, and the like). In a given embodiment,antibodies for NOVX proteins, or derivatives, fragments, analogs orhomologs thereof, that contain the antibody derived binding domain, areutilized as pharmacologically-active compounds (hereinafter“Therapeutics”).

[0565] An anti-NOVX antibody (e.g., monoclonal antibody) can be used toisolate an NOVX polypeptide by standard techniques, such as affinitychromatography or immunoprecipitation. An anti-NOVX antibody canfacilitate the purification of natural NOVX polypeptide from cells andof recombinantly-produced NOVX polypeptide expressed in host cells.Moreover, an anti-NOVX antibody can be used to detect NOVX protein(e.g., in a cellular lysate or cell supernatant) in order to evaluatethe abundance and pattern of expression of the NOVX protein. Anti-NOVXantibodies can be used diagnostically to monitor protein levels intissue as part of a clinical testing procedure, e.g., to, for example,determine the efficacy of a given treatment regimen. Detection can befacilitated by coupling (i.e., physically linking) the antibody to adetectable substance. Examples of detectable substances include variousenzymes, prosthetic groups, fluorescent materials, luminescentmaterials, bioluminescent materials, and radioactive materials. Examplesof suitable enzymes include horseradish peroxidase, alkalinephosphatase, □-galactosidase, or acetylcholinesterase; examples ofsuitable prosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin,and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or³H.

[0566] NOVX Recombinant Expression Vectors and Host Cells

[0567] Another aspect of the invention pertains to vectors, preferablyexpression vectors, containing a nucleic acid encoding an NOVX protein,or derivatives, fragments, analogs or homologs thereof. As used herein,the term “vector” refers to a nucleic acid molecule capable oftransporting another nucleic acid to which it has been linked. One typeof vector is a “plasmid”, which refers to a circular double stranded DNAloop into which additional DNA segments can be ligated. Another type ofvector is a viral vector, wherein additional DNA segments can be ligatedinto the viral genome. Certain vectors are capable of autonomousreplication in a host cell into which they are introduced (e.g.,bacterial vectors having a bacterial origin of replication and episomalmammalian vectors). Other vectors (e.g., non-episomal mammalian vectors)are integrated into the genome of a host cell upon introduction into thehost cell, and thereby are replicated along with the host genome.Moreover, certain vectors are capable of directing the expression ofgenes to which they are operatively-linked. Such vectors are referred toherein as “expression vectors”. In general, expression vectors ofutility in recombinant DNA techniques are often in the form of plasmids.In the present specification, “plasmid” and “vector” can be usedinterchangeably as the plasmid is the most commonly used form of vector.However, the invention is intended to include such other forms ofexpression vectors, such as viral vectors (e.g., replication defectiveretroviruses, adenoviruses and adeno-associated viruses), which serveequivalent functions.

[0568] The recombinant expression vectors of the invention comprise anucleic acid of the invention in a form suitable for expression of thenucleic acid in a host cell, which means that the recombinant expressionvectors include one or more regulatory sequences, selected on the basisof the host cells to be used for expression, that is operatively-linkedto the nucleic acid sequence to be expressed. Within a recombinantexpression vector, “operably-linked” is intended to mean that thenucleotide sequence of interest is linked to the regulatory sequence(s)in a manner that allows for expression of the nucleotide sequence (e.g.,in an in vitro transcription/translation system or in a host cell whenthe vector is introduced into the host cell).

[0569] The term “regulatory sequence” is intended to includes promoters,enhancers and other expression control elements (e.g., polyadenylationsignals). Such regulatory sequences are described, for example, inGoeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, AcademicPress, San Diego, Calif. (1990). Regulatory sequences include those thatdirect constitutive expression of a nucleotide sequence in many types ofhost cell and those that direct expression of the nucleotide sequenceonly in certain host cells (e.g., tissue-specific regulatory sequences).It will be appreciated by those skilled in the art that the design ofthe expression vector can depend on such factors as the choice of thehost cell to be transformed, the level of expression of protein desired,etc. The expression vectors of the invention can be introduced into hostcells to thereby produce proteins or peptides, including fusion proteinsor peptides, encoded by nucleic acids as described herein (e.g., NOVXproteins, mutant forms of NOVX proteins, fusion proteins, etc.).

[0570] The recombinant expression vectors of the invention can bedesigned for expression of NOVX proteins in prokaryotic or eukaryoticcells. For example, NOVX proteins can be expressed in bacterial cellssuch as Escherichia coli, insect cells (using baculovirus expressionvectors) yeast cells or mammalian cells. Suitable host cells arediscussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS INENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively,the recombinant expression vector can be transcribed and translated invitro, for example using T7 promoter regulatory sequences and T7polymerase. Expression of proteins in prokaryotes is most often carriedout in Escherichia coli with vectors containing constitutive orinducible promoters directing the expression of either fusion ornon-fusion proteins. Fusion vectors add a number of amino acids to aprotein encoded therein, usually to the amino terminus of therecombinant protein. Such fusion vectors typically serve three purposes:(i) to increase expression of recombinant protein; (ii) to increase thesolubility of the recombinant protein; and (iii) to aid in thepurification of the recombinant protein by acting as a ligand inaffinity purification. Often, in fusion expression vectors, aproteolytic cleavage site is introduced at the junction of the fusionmoiety and the recombinant protein to enable separation of therecombinant protein from the fusion moiety subsequent to purification ofthe fusion protein. Such enzymes, and their cognate recognitionsequences, include Factor Xa, thrombin and enterokinase. Typical fusionexpression vectors include pGEX (Pharmacia Biotech Inc; Smith andJohnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly,Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathioneS-transferase (GST), maltose E binding protein, or protein A,respectively, to the target recombinant protein. Examples of suitableinducible non-fusion E. coli expression vectors include pTrc (Amrann etal., (1988) Gene 69:301-315) and pET 11d (Studier et al., GENEEXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, SanDiego, Calif. (1990) 60-89).

[0571] One strategy to maximize recombinant protein expression in E.coli is to express the protein in a host bacteria with an impairedcapacity to proteolytically cleave the recombinant protein. See, e.g.,Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185,Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is toalter the nucleic acid sequence of the nucleic acid to be inserted intoan expression vector so that the individual codons for each amino acidare those preferentially utilized in E. coli (see, e.g., Wada, et al.,1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acidsequences of the invention can be carried out by standard DNA synthesistechniques. In another embodiment, the NOVX expression vector is a yeastexpression vector. Examples of vectors for expression in yeastSaccharomyces cerivisae include pYepSecl (Baldari, et al., 1987. EMBO J.6: 229-234), pMa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88(Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation,San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.).

[0572] Alternatively, NOVX can be expressed in insect cells usingbaculovirus expression vectors. Baculovirus vectors available forexpression of proteins in cultured insect cells (e.g., SF9 cells)include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3:2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170:31-39).

[0573] In yet another embodiment, a nucleic acid of the invention isexpressed in mammalian cells using a mammalian expression vector.Examples of mammalian expression vectors include pCDM8 (Seed, 1987.Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195).When used in mammalian cells, the expression vector's control functionsare often provided by viral regulatory elements. For example, commonlyused promoters are derived from polyoma, adenovirus 2, cytomegalovirus,and simian virus 40. For other suitable expression systems for bothprokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 ofSambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., ColdSpring Harbor Laboratory, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 1989. In another embodiment, the recombinantmammalian expression vector is capable of directing expression of thenucleic acid preferentially in a particular cell type (e.g.,tissue-specific regulatory elements are used to express the nucleicacid). Tissue-specific regulatory elements are known in the art.Non-limiting examples of suitable tissue-specific promoters include thealbumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1:268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv.Immunol. 43: 235-275), in particular promoters of T cell receptors(Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins(Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983.Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilamentpromoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86:5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science230: 912-916), and mammary gland-specific promoters (e.g., milk wheypromoter; U.S. Pat. No. 4,873,316 and European Application PublicationNo. 264,166). Developmentally-regulated promoters are also encompassed,e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249:374-379) and the □-fetoprotein promoter (Campes and Tilghman, 1989.Genes Dev. 3: 537-546).

[0574] The invention further provides a recombinant expression vectorcomprising a DNA molecule of the invention cloned into the expressionvector in an antisense orientation. That is, the DNA molecule isoperatively-linked to a regulatory sequence in a manner that allows forexpression (by transcription of the DNA molecule) of an RNA moleculethat is antisense to NOVX mRNA. Regulatory sequences operatively linkedto a nucleic acid cloned in the antisense orientation can be chosen thatdirect the continuous expression of the antisense RNA molecule in avariety of cell types, for instance viral promoters and/or enhancers, orregulatory sequences can be chosen that direct constitutive, tissuespecific or cell type specific expression of antisense RNA. Theantisense expression vector can be in the form of a recombinant plasmid,phagemid or attenuated virus in which antisense nucleic acids areproduced under the control of a high efficiency regulatory region, theactivity of which can be determined by the cell type into which thevector is introduced. For a discussion of the regulation of geneexpression using antisense genes see, e.g., Weintraub, et al.,“Antisense RNA as a molecular tool for genetic analysis,” Reviews-Trendsin Genetics, Vol. 1(1) 1986.

[0575] Another aspect of the invention pertains to host cells into whicha recombinant expression vector of the invention has been introduced.The terms “host cell” and “recombinant host cell” are usedinterchangeably herein. It is understood that such terms refer not onlyto the particular subject cell but also to the progeny or potentialprogeny of such a cell. Because certain modifications may occur insucceeding generations due to either mutation or environmentalinfluences, such progeny may not, in fact, be identical to the parentcell, but are still included within the scope of the term as usedherein.

[0576] A host cell can be any prokaryotic or eukaryotic cell. Forexample, NOVX protein can be expressed in bacterial cells such as E.coli, insect cells, yeast or mammalian cells (such as Chinese hamsterovary cells (CHO) or COS cells). Other suitable host cells are known tothose skilled in the art.

[0577] Vector DNA can be introduced into prokaryotic or eukaryotic cellsvia conventional transformation or transfection techniques. As usedherein, the terms “transformation” and “transfection” are intended torefer to a variety of art-recognized techniques for introducing foreignnucleic acid (e.g., DNA) into a host cell, including calcium phosphateor calcium chloride co-precipitation, DEAE-dextran-mediatedtransfection, lipofection, or electroporation. Suitable methods fortransforming or transfecting host cells can be found in Sambrook, et al.(MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring HarborLaboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y., 1989), and other laboratory manuals.

[0578] For stable transfection of mammalian cells, it is known that,depending upon the expression vector and transfection technique used,only a small fraction of cells may integrate the foreign DNA into theirgenome. In order to identify and select these integrants, a gene thatencodes a selectable marker (e.g., resistance to antibiotics) isgenerally introduced into the host cells along with the gene ofinterest. Various selectable markers include those that conferresistance to drugs, such as G418, hygromycin and methotrexate. Nucleicacid encoding a selectable marker can be introduced into a host cell onthe same vector as that encoding NOVX or can be introduced on a separatevector. Cells stably transfected with the introduced nucleic acid can beidentified by drug selection (e.g., cells that have incorporated theselectable marker gene will survive, while the other cells die).

[0579] A host cell of the invention, such as a prokaryotic or eukaryotichost cell in culture, can be used to produce (Le., express) NOVXprotein. Accordingly, the invention further provides methods forproducing NOVX protein using the host cells of the invention. In oneembodiment, the method comprises culturing the host cell of invention(into which a recombinant expression vector encoding NOVX protein hasbeen introduced) in a suitable medium such that NOVX protein isproduced. In another embodiment, the method further comprises isolatingNOVX protein from the medium or the host cell.

[0580] Transgenic NOVX Animals

[0581] The host cells of the invention can also be used to producenon-human transgenic animals. For example, in one embodiment, a hostcell of the invention is a fertilized oocyte or an embryonic stem cellinto which NOVX protein-coding sequences have been introduced. Such hostcells can then be used to create non-human transgenic animals in whichexogenous NOVX sequences have been introduced into their genome orhomologous recombinant animals in which endogenous NOVX sequences havebeen altered. Such animals are useful for studying the function and/oractivity of NOVX protein and for identifying and/or evaluatingmodulators of NOVX protein activity. As used herein, a “transgenicanimal” is a non-human animal, preferably a mammal, more preferably arodent such as a rat or mouse, in which one or more of the cells of theanimal includes a transgene. Other examples of transgenic animalsinclude non-human primates, sheep, dogs, cows, goats, chickens,amphibians, etc. A transgene is exogenous DNA that is integrated intothe genome of a cell from which a transgenic animal develops and thatremains in the genome of the mature animal, thereby directing theexpression of an encoded gene product in one or more cell types ortissues of the transgenic animal. As used herein, a “homologousrecombinant animal” is a non-human animal, preferably a mammal, morepreferably a mouse, in which an endogenous NOVX gene has been altered byhomologous recombination between the endogenous gene and an exogenousDNA molecule introduced into a cell of the animal, e.g., an embryoniccell of the animal, prior to development of the animal.

[0582] A transgenic animal of the invention can be created byintroducing NOVX-encoding nucleic acid into the male pronuclei of afertilized oocyte (e.g., by microinjection, retroviral infection) andallowing the oocyte to develop in a pseudopregnant female foster animal.The human NOVX cDNA sequences SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53,55, 57, and 59 can be introduced as a transgene into the genome of anon-human animal. Alternatively, a non-human homologue of the human NOVXgene, such as a mouse NOVX gene, can be isolated based on hybridizationto the human NOVX cDNA (described further supra) and used as atransgene. Intronic sequences and polyadenylation signals can also beincluded in the transgene to increase the efficiency of expression ofthe transgene. A tissue-specific regulatory sequence(s) can beoperably-linked to the NOVX transgene to direct expression of NOVXprotein to particular cells. Methods for generating transgenic animalsvia embryo manipulation and microinjection, particularly animals such asmice, have become conventional in the art and are described, forexample, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191; andHogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. Similar methods are used forproduction of other transgenic animals. A transgenic founder animal canbe identified based upon the presence of the NOVX transgene in itsgenome and/or expression of NOVX mRNA in tissues or cells of theanimals. A transgenic founder animal can then be used to breedadditional animals carrying the transgene. Moreover, transgenic animalscarrying a transgene-encoding NOVX protein can further be bred to othertransgenic animals carrying other transgenes.

[0583] To create a homologous recombinant animal, a vector is preparedwhich contains at least a portion of an NOVX gene into which a deletion,addition or substitution has been introduced to thereby alter, e.g.,functionally disrupt, the NOVX gene. The NOVX gene can be a human gene(e.g., the cDNA of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57,and 59), but more preferably, is a non-human homologue of a human NOVXgene. For example, a mouse homologue of human NOVX gene of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37,39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59 can be used to constructa homologous recombination vector suitable for altering an endogenousNOVX gene in the mouse genome. In one embodiment, the vector is designedsuch that, upon homologous recombination, the endogenous NOVX gene isfunctionally disrupted (i.e., no longer encodes a functional protein;also referred to as a “knock out” vector).

[0584] Alternatively, the vector can be designed such that, uponhomologous recombination, the endogenous NOVX gene is mutated orotherwise altered but still encodes functional protein (e.g., theupstream regulatory region can be altered to thereby alter theexpression of the endogenous NOVX protein). In the homologousrecombination vector, the altered portion of the NOVX gene is flanked atits 5′- and 3′-termini by additional nucleic acid of the NOVX gene toallow for homologous recombination to occur between the exogenous NOVXgene carried by the vector and an endogenous NOVX gene in an embryonicstem cell. The additional flanking NOVX nucleic acid is of sufficientlength for successful homologous recombination with the endogenous gene.Typically, several kilobases of flanking DNA (both at the 5′- and3′-termini) are included in the vector. See, e.g., Thomas, et al., 1987.Cell 51: 503 for a description of homologous recombination vectors. Thevector is ten introduced into an embryonic stem cell line (e.g., byelectroporation) and cells in which the introduced NOVX gene hashomologously-recombined with the endogenous NOVX gene are selected. See,e.g., Li, et al., 1992. Cell 69: 915.

[0585] The selected cells are then injected into a blastocyst of ananimal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley,1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICALAPPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo canthen be implanted into a suitable pseudopregnant female foster animaland the embryo brought to term. Progeny harboring thehomologously-recombined DNA in their germ cells can be used to breedanimals in which all cells of the animal contain thehomologously-recombined DNA by germline transmission of the transgene.Methods for constructing homologous recombination vectors and homologousrecombinant animals are described further in Bradley, 1991. Curr. Opin.Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354;WO 91/01140; WO 92/0968; and WO 93/04169.

[0586] In another embodiment, transgenic non-humans animals can beproduced that contain selected systems that allow for regulatedexpression of the transgene. One example of such a system is thecre/loxP recombinase system of bacteriophage P1. For a description ofthe cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc.Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinasesystem is the FLP recombinase system of Saccharomyces cerevisiae. See,O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinasesystem is used to regulate expression of the transgene, animalscontaining transgenes encoding both the Cre recombinase and a selectedprotein are required. Such animals can be provided through theconstruction of “double” transgenic animals, e.g., by mating twotransgenic animals, one containing a transgene encoding a selectedprotein and the other containing a transgene encoding a recombinase.

[0587] Clones of the non-human transgenic animals described herein canalso be produced according to the methods described in Wilmut, et al.,1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) fromthe transgenic animal can be isolated and induced to exit the growthcycle and enter G₀ phase. The quiescent cell can then be fused, e.g.,through the use of electrical pulses, to an enucleated oocyte from ananimal of the same species from which the quiescent cell is isolated.The reconstructed oocyte is then cultured such that it develops tomorula or blastocyte and then transferred to pseudopregnant femalefoster animal. The offspring borne of this female foster animal will bea clone of the animal from which the cell (e.g., the somatic cell) isisolated.

[0588] Pharmaceutical Compositions

[0589] The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVXantibodies (also referred to herein as “active compounds”) of theinvention, and derivatives, fragments, analogs and homologs thereof, canbe incorporated into pharmaceutical compositions suitable foradministration. Such compositions typically comprise the nucleic acidmolecule, protein, or antibody and a pharmaceutically acceptablecarrier. As used herein, “pharmaceutically acceptable carrier” isintended to include any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration.Suitable carriers are described in the most recent edition ofRemington's Pharmaceutical Sciences, a standard reference text in thefield, which is incorporated herein by reference. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

[0590] A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical),transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

[0591] Pharmaceutical compositions suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

[0592] Sterile injectable solutions can be prepared by incorporating theactive compound (e.g., an NOVX protein or anti-NOVX antibody) in therequired amount in an appropriate solvent with one or a combination ofingredients enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating theactive compound into a sterile vehicle that contains a basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, methods of preparation are vacuum drying and freeze-dryingthat yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.

[0593] Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

[0594] For administration by inhalation, the compounds are delivered inthe form of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

[0595] Systemic administration can also be by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, detergents, bilesalts, and fusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

[0596] The compounds can also be prepared in the form of suppositories(e.g., with conventional suppository bases such as cocoa butter andother glycerides) or retention enemas for rectal delivery.

[0597] In one embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0598] It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals.

[0599] The nucleic acid molecules of the invention can be inserted intovectors and used as gene therapy vectors. Gene therapy vectors can bedelivered to a subject by, for example, intravenous injection, localadministration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotacticinjection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vectorcan include the gene therapy vector in an acceptable diluent, or cancomprise a slow release matrix in which the gene delivery vehicle isimbedded. Alternatively, where the complete gene delivery vector can beproduced intact from recombinant cells, e.g., retroviral vectors, thepharmaceutical preparation can include one or more cells that producethe gene delivery system.

[0600] The pharmaceutical compositions can be included in a container,pack, or dispenser together with instructions for administration.

[0601] Screening and Detection Methods

[0602] The isolated nucleic acid molecules of the invention can be usedto express NOVX protein (e.g., via a recombinant expression vector in ahost cell in gene therapy applications), to detect NOVX mRNA (e.g., in abiological sample) or a genetic lesion in an NOVX gene, and to modulateNOVX activity, as described further, below. In addition, the NOVXproteins can be used to screen drugs or compounds that modulate the NOVXprotein activity or expression as well as to treat disorderscharacterized by insufficient or excessive production of NOVX protein orproduction of NOVX protein forms that have decreased or aberrantactivity compared to NOVX wild-type protein (e.g.; diabetes (regulatesinsulin release); obesity (binds and transport lipids); metabolicdisturbances associated with obesity, the metabolic syndrome X as wellas anorexia and wasting disorders associated with chronic diseases andvarious cancers, and infectious disease(possesses anti-microbialactivity) and the various dyslipidemias. In addition, the anti-NOVXantibodies of the invention can be used to detect and isolate NOVXproteins and modulate NOVX activity. In yet a further aspect, theinvention can be used in methods to influence appetite, absorption ofnutrients and the disposition of metabolic substrates in both a positiveand negative fashion.

[0603] The invention further pertains to novel agents identified by thescreening assays described herein and uses thereof for treatments asdescribed, supra.

[0604] Screening Assays

[0605] The invention provides a method (also referred to herein as a“screening assay”) for identifying modulators, ie., candidate or testcompounds or agents (e.g., peptides, peptidomimetics, small molecules orother drugs) that bind to NOVX proteins or have a stimulatory orinhibitory effect on, e.g., NOVX protein expression or NOVX proteinactivity. The invention also includes compounds identified in thescreening assays described herein. In one embodiment, the inventionprovides assays for screening candidate or test compounds which bind toor modulate the activity of the membrane-bound form of an NOVX proteinor polypeptide or biologically-active portion thereof. The testcompounds of the invention can be obtained using any of the numerousapproaches in combinatorial library methods known in the art, including:biological libraries; spatially addressable parallel solid phase orsolution phase libraries; synthetic library methods requiringdeconvolution; the “one-bead one-compound” library method; and syntheticlibrary methods using affinity chromatography selection. The biologicallibrary approach is limited to peptide libraries, while the other fourapproaches are applicable to peptide, non-peptide oligomer or smallmolecule libraries of compounds. See, e.g., Lam, 1997. Anticancer DrugDesign 12:145.

[0606] A “small molecule” as used herein, is meant to refer to acomposition that has a molecular weight of less than about 5 kD and mostpreferably less than about 4 kD. Small molecules can be, e.g., nucleicacids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids orother organic or inorganic molecules. Libraries of chemical and/orbiological mixtures, such as fungal, bacterial, or algal extracts, areknown in the art and can be screened with any of the assays of theinvention.

[0607] Examples of methods for the synthesis of molecular libraries canbe found in the art, for example in: DeWitt, et al., 1993. Proc. Natl.Acad. Sci. U.S.A. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad. Sci.U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho,et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem.Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed.Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37:1233.

[0608] Libraries of compounds may be presented in solution (e.g.,Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991.Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556),bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat.No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390;Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl.Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222:301-310; Ladner, U.S. Pat. No. 5,233,409.).

[0609] In one embodiment, an assay is a cell-based assay in which a cellwhich expresses a membrane-bound form of NOVX protein, or abiologically-active portion thereof, on the cell surface is contactedwith a test compound and the ability of the test compound to bind to anNOVX protein determined. The cell, for example, can of mammalian originor a yeast cell. Determining the ability of the test compound to bind tothe NOVX protein can be accomplished, for example, by coupling the testcompound with a radioisotope or enzymatic label such that binding of thetest compound to the NOVX protein or biologically-active portion thereofcan be determined by detecting the labeled compound in a complex. Forexample, test compounds can be labeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H,either directly or indirectly, and the radioisotope detected by directcounting of radioemission or by scintillation counting. Alternatively,test compounds can be enzymatically-labeled with, for example,horseradish peroxidase, alkaline phosphatase, or luciferase, and theenzymatic label detected by determination of conversion of anappropriate substrate to product. In one embodiment, the assay comprisescontacting a cell which expresses a membrane-bound form of NOVX protein,or a biologically-active portion thereof, on the cell surface with aknown compound which binds NOVX to form an assay mixture, contacting theassay mixture with a test compound, and determining the ability of thetest compound to interact with an NOVX protein, wherein determining theability of the test compound to interact with an NOVX protein comprisesdetermining the ability of the test compound to preferentially bind toNOVX protein or a biologically-active portion thereof as compared to theknown compound.

[0610] In another embodiment, an assay is a cell-based assay comprisingcontacting a cell expressing a membrane-bound form of NOVX protein, or abiologically-active portion thereof, on the cell surface with a testcompound and determining the ability of the test compound to modulate(e.g., stimulate or inhibit) the activity of the NOVX protein orbiologically-active portion thereof. Determining the ability of the testcompound to modulate the activity of NOVX or a biologically-activeportion thereof can be accomplished, for example, by determining theability of the NOVX protein to bind to or interact with an NOVX targetmolecule. As used herein, a “target molecule” is a molecule with whichan NOVX protein binds or interacts in nature, for example, a molecule onthe surface of a cell which expresses an NOVX interacting protein, amolecule on the surface of a second cell, a molecule in theextracellular milieu, a molecule associated with the internal surface ofa cell membrane or a cytoplasmic molecule. An NOVX target molecule canbe a non-NOVX molecule or an NOVX protein or polypeptide of theinvention. In one embodiment, an NOVX target molecule is a component ofa signal transduction pathway that facilitates transduction of anextracellular signal (e.g. a signal generated by binding of a compoundto a membrane-bound NOVX molecule) through the cell membrane and intothe cell. The target, for example, can be a second intercellular proteinthat has catalytic activity or a protein that facilitates theassociation of downstream signaling molecules with NOVX.

[0611] Determining the ability of the NOVX protein to bind to orinteract with an NOVX target molecule can be accomplished by one of themethods described above for determining direct binding. In oneembodiment, determining the ability of the NOVX protein to bind to orinteract with an NOVX target molecule can be accomplished by determiningthe activity of the target molecule. For example, the activity of thetarget molecule can be determined by detecting induction of a cellularsecond messenger of the target (i.e. intracellular Ca²⁺, diacylglycerol,IP₃, etc.), detecting catalytic/enzymatic activity of the target anappropriate substrate, detecting the induction of a reporter gene(comprising an NOVX-responsive regulatory element operatively linked toa nucleic acid encoding a detectable marker, e.g., luciferase), ordetecting a cellular response, for example, cell survival, cellulardifferentiation, or cell proliferation.

[0612] In yet another embodiment, an assay of the invention is acell-free assay comprising contacting an NOVX protein orbiologically-active portion thereof with a test compound and determiningthe ability of the test compound to bind to the NOVX protein orbiologically-active portion thereof. Binding of the test compound to theNOVX protein can be determined either directly or indirectly asdescribed above. In one such embodiment, the assay comprises contactingthe NOVX protein or biologically-active portion thereof with a knowncompound which binds NOVX to form an assay mixture, contacting the assaymixture with a test compound, and determining the ability of the testcompound to interact with an NOVX protein, wherein determining theability of the test compound to interact with an NOVX protein comprisesdetermining the ability of the test compound to preferentially bind toNOVX or biologically-active portion thereof as compared to the knowncompound.

[0613] In still another embodiment, an assay is a cell-free assaycomprising contacting NOVX protein or biologically-active portionthereof with a test compound and determining the ability of the testcompound to modulate (e.g. stimulate or inhibit) the activity of theNOVX protein or biologically-active portion thereof. Determining theability of the test compound to modulate the activity of NOVX can beaccomplished, for example, by determining the ability of the NOVXprotein to bind to an NOVX target molecule by one of the methodsdescribed above for determining direct binding. In an alternativeembodiment, determining the ability of the test compound to modulate theactivity of NOVX protein can be accomplished by determining the abilityof the NOVX protein further modulate an NOVX target molecule. Forexample, the catalytic/enzymatic activity of the target molecule on anappropriate substrate can be determined as described, supra.

[0614] In yet another embodiment, the cell-free assay comprisescontacting the NOVX protein or biologically-active portion thereof witha known compound which binds NOVX protein to form an assay mixture,contacting the assay mixture with a test compound, and determining theability of the test compound to interact with an NOVX protein, whereindetermining the ability of the test compound to interact with an NOVXprotein comprises determining the ability of the NOVX protein topreferentially bind to or modulate the activity of an NOVX targetmolecule.

[0615] The cell-free assays of the invention are amenable to use of boththe soluble form or the membrane-bound form of NOVX protein. In the caseof cell-free assays comprising the membrane-bound form of NOVX protein,it may be desirable to utilize a solubilizing agent such that themembrane-bound form of NOVX protein is maintained in solution. Examplesof such solubilizing agents include non-ionic detergents such asn-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside,octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100,Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)_(n),N-dodecyl-N,N-dimethyl-3-ammonio-1-propane sulfonate,3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate(CHAPSO). In more than one embodiment of the above assay methods of theinvention, it may be desirable to immobilize either NOVX protein or itstarget molecule to facilitate separation of complexed from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Binding of a test compound to NOVX protein, orinteraction of NOVX protein with a target molecule in the presence andabsence of a candidate compound, can be accomplished in any vesselsuitable for containing the reactants. Examples of such vessels includemicrotiter plates, test tubes, and micro-centrifuge tubes. In oneembodiment, a fusion protein can be provided that adds a domain thatallows one or both of the proteins to be bound to a matrix. For example,GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbedonto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) orglutathione derivatized microtiter plates, that are then combined withthe test compound or the test compound and either the non-adsorbedtarget protein or NOVX protein, and the mixture is incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads ormicrotiter plate wells are washed to remove any unbound components, thematrix immobilized in the case of beads, complex determined eitherdirectly or indirectly, for example, as described, supra. Alternatively,the complexes can be dissociated from the matrix, and the level of NOVXprotein binding or activity determined using standard techniques.

[0616] Other techniques for immobilizing proteins on matrices can alsobe used in the screening assays of the invention. For example, eitherthe NOVX protein or its target molecule can be immobilized utilizingconjugation of biotin and streptavidin. Biotinylated NOVX protein ortarget molecules can be prepared from biotin-NHS (N-hydroxy-succinimide)using techniques well-known within the art (e.g., biotinylation kit,Pierce Chemicals, Rockford, Ill.), and immobilized in the wells ofstreptavidin-coated 96 well plates (Pierce Chemical). Alternatively,antibodies reactive with NOVX protein or target molecules, but which donot interfere with binding of the NOVX protein to its target molecule,can be derivatized to the wells of the plate, and unbound target or NOVXprotein trapped in the wells by antibody conjugation. Methods fordetecting such complexes, in addition to those described above for theGST-immobilized complexes, include immunodetection of complexes usingantibodies reactive with the NOVX protein or target molecule, as well asenzyme-linked assays that rely on detecting an enzymatic activityassociated with the NOVX protein or target molecule.

[0617] In another embodiment, modulators of NOVX protein expression areidentified in a method wherein a cell is contacted with a candidatecompound and the expression of NOVX mRNA or protein in the cell isdetermined. The level of expression of NOVX mRNA or protein in thepresence of the candidate compound is compared to the level ofexpression of NOVX mRNA or protein in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof NOVX mRNA or protein expression based upon this comparison. Forexample, when expression of NOVX mRNA or protein is greater (ie.,statistically significantly greater) in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of NOVX mRNA or protein expression. Alternatively, whenexpression of NOVX mRNA or protein is less (statistically significantlyless) in the presence of the candidate compound than in its absence, thecandidate compound is identified as an inhibitor of NOVX mRNA or proteinexpression. The level of NOVX mRNA or protein expression in the cellscan be determined by methods described herein for detecting NOVX mRNA orprotein.

[0618] In yet another aspect of the invention, the NOVX proteins can beused as “bait proteins” in a two-hybrid assay or three hybrid assay(see, e.g., U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72:223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel,et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993.Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify otherproteins that bind to or interact with NOVX (“NOVX-binding proteins” or“NOVX-bp”) and modulate NOVX activity. Such NOVX-binding proteins arealso likely to be involved in the propagation of signals by the NOVXproteins as, for example, upstream or downstream elements of the NOVXpathway. The two-hybrid system is based on the modular nature of mosttranscription factors, which consist of separable DNA-binding andactivation domains. Briefly, the assay utilizes two different DNAconstructs. In one construct, the gene that codes for NOVX is fused to agene encoding the DNA binding domain of a known transcription factor(e.g., GAL-4). In the other construct, a DNA sequence, from a library ofDNA sequences, that encodes an unidentified protein (“prey” or “sample”)is fused to a gene that codes for the activation domain of the knowntranscription factor. If the “bait” and the “prey” proteins are able tointeract, in vivo, forming an NOVX-dependent complex, the DNA-bindingand activation domains of the transcription factor are brought intoclose proximity. This proximity allows transcription of a reporter gene(e.g., LacZ) that is operably linked to a transcriptional regulatorysite responsive to the transcription factor. Expression of the reportergene can be detected and cell colonies containing the functionaltranscription factor can be isolated and used to obtain the cloned genethat encodes the protein which interacts with NOVX.

[0619] The invention further pertains to novel agents identified by theaforementioned screening assays and uses thereof for treatments asdescribed herein.

[0620] Detection Assays

[0621] Portions or fragments of the cDNA sequences identified herein(and the corresponding complete gene sequences) can be used in numerousways as polynucleotide reagents. By way of example, and not oflimitation, these sequences can be used to: (i) map their respectivegenes on a chromosome; and, thus, locate gene regions associated withgenetic disease; (ii) identify an individual from a minute biologicalsample (tissue typing); and (iii) aid in forensic identification of abiological sample. Some of these applications are described in thesubsections, below.

[0622] Chromosome Mapping

[0623] Once the sequence (or a portion of the sequence) of a gene hasbeen isolated, this sequence can be used to map the location of the geneon a chromosome. This process is called chromosome mapping. Accordingly,portions or fragments of the NOVX sequences, SEQ ID NOS: 1, 3, 5, 7, 9,11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45,47, 49, 51, 53, 55, 57, and 59, or fragments or derivatives thereof, canbe used to map the location of the NOVX genes, respectively, on achromosome. The mapping of the NOVX sequences to chromosomes is animportant first step in correlating these sequences with genesassociated with disease.

[0624] Briefly, NOVX genes can be mapped to chromosomes by preparing PCRprimers (preferably 15-25 bp in length) from the NOVX sequences.Computer analysis of the NOVX, sequences can be used to rapidly selectprimers that do not span more than one exon in the genomic DNA, thuscomplicating the amplification process. These primers can then be usedfor PCR screening of somatic cell hybrids containing individual humanchromosomes. Only those hybrids containing the human gene correspondingto the NOVX sequences will yield an amplified fragment.

[0625] Somatic cell hybrids are prepared by fusing somatic cells fromdifferent mammals (e.g., human and mouse cells). As hybrids of human andmouse cells grow and divide, they gradually lose human chromosomes inrandom order, but retain the mouse chromosomes. By using media in whichmouse cells cannot grow, because they lack a particular enzyme, but inwhich human cells can, the one human chromosome that contains the geneencoding the needed enzyme will be retained. By using various media,panels of hybrid cell lines can be established. Each cell line in apanel contains either a single human chromosome or a small number ofhuman chromosomes, and a full set of mouse chromosomes, allowing easymapping of individual genes to specific human chromosomes. See, e.g.,D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybridscontaining only fragments of human chromosomes can also be produced byusing human chromosomes with translocations and deletions.

[0626] PCR mapping of somatic cell hybrids is a rapid procedure forassigning a particular sequence to a particular chromosome. Three ormore sequences can be assigned per day using a single thermal cycler.Using the NOVX sequences to design oligonucleotide primers,sub-localization can be achieved with panels of fragments from specificchromosomes.

[0627] Fluorescence in situ hybridization (FISH) of a DNA sequence to ametaphase chromosomal spread can further be used to provide a precisechromosomal location in one step. Chromosome spreads can be made usingcells whose division has been blocked in metaphase by a chemical likecolcemid that disrupts the mitotic spindle. The chromosomes can betreated briefly with trypsin, and then stained with Giemsa. A pattern oflight and dark bands develops on each chromosome, so that thechromosomes can be identified individually. The FISH technique can beused with a DNA sequence as short as 500 or 600 bases. However, cloneslarger than 1,000 bases have a higher likelihood of binding to a uniquechromosomal location with sufficient signal intensity for simpledetection. Preferably 1,000 bases, and more preferably 2,000 bases, willsuffice to get good results at a reasonable amount of time. For a reviewof this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OFBASIC TECHNIQUES (Pergamon Press, New York 1988).

[0628] Reagents for chromosome mapping can be used individually to marka single chromosome or a single site on that chromosome, or panels ofreagents can be used for marking multiple sites and/or multiplechromosomes. Reagents corresponding to noncoding regions of the genesactually are preferred for mapping purposes. Coding sequences are morelikely to be conserved within gene families, thus increasing the chanceof cross hybridizations during chromosomal mapping.

[0629] Once a sequence has been mapped to a precise chromosomallocation, the physical position of the sequence on the chromosome can becorrelated with genetic map data. Such data are found, e.g., inMcKusick, MENDELIAN INHERITANCE IN MAN, available on-line through JohnsHopkins University Welch Medical Library). The relationship betweengenes and disease, mapped to the same chromosomal region, can then beidentified through linkage analysis (co-inheritance of physicallyadjacent genes), described in, e.g., Egeland, et al., 1987. Nature, 325:783-787.

[0630] Moreover, differences in the DNA sequences between individualsaffected and unaffected with a disease associated with the NOVX gene,can be determined. If a mutation is observed in some or all of theaffected individuals but not in any unaffected individuals, then themutation is likely to be the causative agent of the particular disease.Comparison of affected and unaffected individuals generally involvesfirst looking for structural alterations in the chromosomes, such asdeletions or translocations that are visible from chromosome spreads ordetectable using PCR based on that DNA sequence. Ultimately, completesequencing of genes from several individuals can be performed to confirmthe presence of a mutation and to distinguish mutations frompolymorphisms.

[0631] Tissue Typing

[0632] The NOVX sequences of the invention can also be used to identifyindividuals from minute biological samples. In this technique, anindividual's genomic DNA is digested with one or more restrictionenzymes, and probed on a Southern blot to yield unique bands foridentification. The sequences of the invention are useful as additionalDNA markers for RFLP (“restriction fragment length polymorphisms,”described in U.S. Pat. No. 5,272,057). Furthermore, the sequences of theinvention can be used to provide an alternative technique thatdetermines the actual base-by-base DNA sequence of selected portions ofan individual's genome. Thus, the NOVX sequences described herein can beused to prepare two PCR primers from the 5′- and 3′-termini of thesequences. These primers can then be used to amplify an individual's DNAand subsequently sequence it.

[0633] Panels of corresponding DNA sequences from individuals, preparedin this manner, can provide unique individual identifications, as eachindividual will have a unique set of such DNA sequences due to allelicdifferences. The sequences of the invention can be used to obtain suchidentification sequences from individuals and from tissue. The NOVXsequences of the invention uniquely represent portions of the humangenome. Allelic variation occurs to some degree in the coding regions ofthese sequences, and to a greater degree in the noncoding regions. It isestimated that allelic variation between individual humans occurs with afrequency of about once per each 500 bases. Much of the allelicvariation is due to single nucleotide polymorphisms (SNPs), whichinclude restriction fragment length polymorphisms (RFLPs).

[0634] Each of the sequences described herein can, to some degree, beused as a standard against which DNA from an individual can be comparedfor identification purposes. Because greater numbers of polymorphismsoccur in the noncoding regions, fewer sequences are necessary todifferentiate individuals. The noncoding sequences can comfortablyprovide positive individual identification with a panel of perhaps 10 to1,000 primers that each yield a noncoding amplified sequence of 100bases. If predicted coding sequences, such as those in SEQ ID NOS: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,43, 45, 47, 49, 51, 53, 55, 57, and 59 are used, a more appropriatenumber of primers for positive individual identification would be500-2,000.

[0635] Predictive Medicine

[0636] The invention also pertains to the field of predictive medicinein which diagnostic assays, prognostic assays, pharmacogenomics, andmonitoring clinical trials are used for prognostic (predictive) purposesto thereby treat an individual prophylactically. Accordingly, one aspectof the invention relates to diagnostic assays for determining NOVXprotein and/or nucleic acid expression as well as NOVX activity, in thecontext of a biological sample (e.g., blood, serum, cells, tissue) tothereby determine whether an individual is afflicted with a disease ordisorder, or is at risk of developing a disorder, associated withaberrant NOVX expression or activity. The disorders include metabolicdisorders, diabetes, obesity, infectious disease, anorexia,cancer-associated cachexia, cancer, neurodegenerative disorders,Alzheimer's Disease, Parkinson's Disorder, immune disorders, andhematopoietic disorders, and the various dyslipidemias, metabolicdisturbances associated with obesity, the metabolic syndrome X andwasting disorders associated with chronic diseases and various cancers.The invention also provides for prognostic (or predictive) assays fordetermining whether an individual is at risk of developing a disorderassociated with NOVX protein, nucleic acid expression or activity. Forexample, mutations in an NOVX gene can be assayed in a biologicalsample. Such assays can be used for prognostic or predictive purpose tothereby prophylactically treat an individual prior to the onset of adisorder characterized by or associated with NOVX protein, nucleic acidexpression, or biological activity.

[0637] Another aspect of the invention provides methods for determiningNOVX protein, nucleic acid expression or activity in an individual tothereby select appropriate therapeutic or prophylactic agents for thatindividual (referred to herein as “pharmacogenomics”). Pharmacogenomicsallows for the selection of agents (e.g., drugs) for therapeutic orprophylactic treatment of an individual based on the genotype of theindividual (e.g., the genotype of the individual examined to determinethe ability of the individual to respond to a particular agent.)

[0638] Yet another aspect of the invention pertains to monitoring theinfluence of agents (e.g., drugs, compounds) on the expression oractivity of NOVX in clinical trials. These and other agents aredescribed in further detail in the following sections.

[0639] Diagnostic Assays

[0640] An exemplary method for detecting the presence or absence of NOVXin a biological sample involves obtaining a biological sample from atest subject and contacting the biological sample with a compound or anagent capable of detecting NOVX protein or nucleic acid (e.g., mRNA,genomic DNA) that encodes NOVX protein such that the presence of NOVX isdetected in the biological sample. An agent for detecting NOVX mRNA orgenomic DNA is a labeled nucleic acid probe capable of hybridizing toNOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, afull-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37,39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, or a portion thereof,such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500nucleotides in length and sufficient to specifically hybridize understringent conditions to NOVX mRNA or genomic DNA. Other suitable probesfor use in the diagnostic assays of the invention are described herein.

[0641] An agent for detecting NOVX protein is an antibody capable ofbinding to NOVX protein, preferably an antibody with a detectable label.Antibodies can be polyclonal, or more preferably, monoclonal. An intactantibody, or a fragment thereof (e.g., Fab or F(ab′)₂) can be used. Theterm “labeled”, with regard to the probe or antibody, is intended toencompass direct labeling of the probe or antibody by coupling (i.e.,physically linking) a detectable substance to the probe or antibody, aswell as indirect labeling of the probe or antibody by reactivity withanother reagent that is directly labeled. Examples of indirect labelinginclude detection of a primary antibody using a fluorescently-labeledsecondary antibody and end-labeling of a DNA probe with biotin such thatit can be detected with fluorescently-labeled streptavidin. The term“biological sample” is intended to include tissues, cells and biologicalfluids isolated from a subject, as well as tissues, cells and fluidspresent within a subject. That is, the detection method of the inventioncan be used to detect NOVX mRNA, protein, or genomic DNA in a biologicalsample in vitro as well as in vivo. For example, in vitro techniques fordetection of NOVX mRNA include Northern hybridizations and in situhybridizations. In vitro techniques for detection of NOVX proteininclude enzyme linked immunosorbent assays (ELISAs), Western blots,immunoprecipitations, and immunofluorescence. In vitro techniques fordetection of NOVX genomic DNA include Southern hybridizations.Furthermore, in vivo techniques for detection of NOVX protein includeintroducing into a subject a labeled anti-NOVX antibody. For example,the antibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

[0642] In one embodiment, the biological sample contains proteinmolecules from the test subject. Alternatively, the biological samplecan contain mRNA molecules from the test subject or genomic DNAmolecules from the test subject. A preferred biological sample is aperipheral blood leukocyte sample isolated by conventional means from asubject.

[0643] In another embodiment, the methods further involve obtaining acontrol biological sample from a control subject, contacting the controlsample with a compound or agent capable of detecting NOVX protein, mRNA,or genomic DNA, such that the presence of NOVX protein, mRNA or genomicDNA is detected in the biological sample, and comparing the presence ofNOVX protein, mRNA or genomic DNA in the control sample with thepresence of NOVX protein, mRNA or genomic DNA in the test sample.

[0644] The invention also encompasses kits for detecting the presence ofNOVX in a biological sample. For example, the kit can comprise: alabeled compound or agent capable of detecting NOVX protein or mRNA in abiological sample; means for determining the amount of NOVX in thesample; and means for comparing the amount of NOVX in the sample with astandard. The compound or agent can be packaged in a suitable container.The kit can further comprise instructions for using the kit to detectNOVX protein or nucleic acid.

[0645] Prognostic Assays

[0646] The diagnostic methods described herein can furthermore beutilized to identify subjects having or at risk of developing a diseaseor disorder associated with aberrant NOVX expression or activity. Forexample, the assays described herein, such as the preceding diagnosticassays or the following assays, can be utilized to identify a subjecthaving or at risk of developing a disorder associated with NOVX protein,nucleic acid expression or activity. Alternatively, the prognosticassays can be utilized to identify a subject having or at risk fordeveloping a disease or disorder. Thus, the invention provides a methodfor identifying a disease or disorder associated with aberrant NOVXexpression or activity in which a test sample is obtained from a subjectand NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected,wherein the presence of NOVX protein or nucleic acid is diagnostic for asubject having or at risk of developing a disease or disorder associatedwith aberrant NOVX expression or activity. As used herein, a “testsample” refers to a biological sample obtained from a subject ofinterest. For example, a test sample can be a biological fluid (e.g.,serum), cell sample, or tissue.

[0647] Furthermore, the prognostic assays described herein can be usedto determine whether a subject can be administered an agent (e.g., anagonist, antagonist, peptidomimetic, protein, peptide, nucleic acid,small molecule, or other drug candidate) to treat a disease or disorderassociated with aberrant NOVX expression or activity. For example, suchmethods can be used to determine whether a subject can be effectivelytreated with an agent for a disorder. Thus, the invention providesmethods for determining whether a subject can be effectively treatedwith an agent for a disorder associated with aberrant NOVX expression oractivity in which a test sample is obtained and NOVX protein or nucleicacid is detected (e.g., wherein the presence of NOVX protein or nucleicacid is diagnostic for a subject that can be administered the agent totreat a disorder associated with aberrant NOVX expression or activity).

[0648] The methods of the invention can also be used to detect geneticlesions in an NOVX gene, thereby determining if a subject with thelesioned gene is at risk for a disorder characterized by aberrant cellproliferation and/or differentiation. In various embodiments, themethods include detecting, in a sample of cells from the subject, thepresence or absence of a genetic lesion characterized by at least one ofan alteration affecting the integrity of a gene encoding anNOVX-protein, or the misexpression of the NOVX gene. For example, suchgenetic lesions can be detected by ascertaining the existence of atleast one of: (i) a deletion of one or more nucleotides from an NOVXgene; (ii) an addition of one or more nucleotides to an NOVX gene; (iii)a substitution of one or more nucleotides of an NOVX gene, (iv) achromosomal rearrangement of an NOVX gene; (v) an alteration in thelevel of a messenger RNA transcript of an NOVX gene, (vi) aberrantmodification of an NOVX gene, such as of the methylation pattern of thegenomic DNA, (vii) the presence of a non-wild-type splicing pattern of amessenger RNA transcript of an NOVX gene, (viii) a non-wild-type levelof an NOVX protein, (ix) allelic loss of an NOVX gene, and (x)inappropriate post-translational modification of an NOVX protein. Asdescribed herein, there are a large number of assay techniques known inthe art which can be used for detecting lesions in an NOVX gene. Apreferred biological sample is a peripheral blood leukocyte sampleisolated by conventional means from a subject. However, any biologicalsample containing nucleated cells may be used, including, for example,buccal mucosal cells.

[0649] In certain embodiments, detection of the lesion involves the useof a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S.Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or,alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran,et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc.Natl. Acad. Sci. USA 91: 360-364), the latter of which can beparticularly useful for detecting point mutations in the NOVX-gene (see,Abravaya, et al., 1995. Nucl. Acids Res. 23: 675-682). This method caninclude the steps of collecting a sample of cells from a patient,isolating nucleic acid (e.g., genomic, mRNA or both) from the cells ofthe sample, contacting the nucleic acid sample with one or more primersthat specifically hybridize to an NOVX gene under conditions such thathybridization and amplification of the NOVX gene (if present) occurs,and detecting the presence or absence of an amplification product, ordetecting the size of the amplification product and comparing the lengthto a control sample. It is anticipated that PCR and/or LCR may bedesirable to use as a preliminary amplification step in conjunction withany of the techniques used for detecting mutations described herein.Alternative amplification methods include: self sustained sequencereplication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (see, Kwoh, et al.,1989. Proc. Natl. Acad. Sci USA 86: 1173-1177); Qβ Replicase (see,Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acidamplification method, followed by the detection of the amplifiedmolecules using techniques well known to those of skill in the art.These detection schemes are especially useful for the detection ofnucleic acid molecules if such molecules are present in very lownumbers.

[0650] In an alternative embodiment, mutations in an NOVX gene from asample cell can be identified by alterations in restriction enzymecleavage patterns. For example, sample and control DNA is isolated,amplified (optionally), digested with one or more restrictionendonucleases, and fragment length sizes are determined by gelelectrophoresis and compared. Differences in fragment length sizesbetween sample and control DNA indicates mutations in the sample DNA.Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Pat.No. 5,493,531) can be used to score for the presence of specificmutations by development or loss of a ribozyme cleavage site.

[0651] In other embodiments, genetic mutations in NOVX can be identifiedby hybridizing a sample and control nucleic acids, e.g., DNA or RNA, tohigh-density arrays containing hundreds or thousands of oligonucleotidesprobes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255;Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, geneticmutations in NOVX can be identified in two dimensional arrays containinglight-generated DNA probes as described in Cronin, et al., supra.Briefly, a first hybridization array of probes can be used to scanthrough long stretches of DNA in a sample and control to identify basechanges between the sequences by making linear arrays of sequentialoverlapping probes. This step allows the identification of pointmutations. This is followed by a second hybridization array that allowsthe characterization of specific mutations by using smaller, specializedprobe arrays complementary to all variants or mutations detected. Eachmutation array is composed of parallel probe sets, one complementary tothe wild-type gene and the other complementary to the mutant gene.

[0652] In yet another embodiment, any of a variety of sequencingreactions known in the art can be used to directly sequence the NOVXgene and detect mutations by comparing the sequence of the sample NOVXwith the corresponding wild-type (control) sequence. Examples ofsequencing reactions include those based on techniques developed byMaxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger,1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated thatany of a variety of automated sequencing procedures can be utilized whenperforming the diagnostic assays (see, e.g., Naeve, et al., 1995.Biotechniques 19: 448), including sequencing by mass spectrometry (see,e.g., PCT International Publication No. WO 94/16101; Cohen, et al.,1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl.Biochem. Biotechnol. 38: 147-159).

[0653] Other methods for detecting mutations in the NOVX gene includemethods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers,et al., 1985. Science 230: 1242. In general, the art technique of“mismatch cleavage” starts by providing heteroduplexes of formed byhybridizing (labeled) RNA or DNA containing the wild-type NOVX sequencewith potentially mutant RNA or DNA obtained from a tissue sample. Thedouble-stranded duplexes are treated with an agent that cleavessingle-stranded regions of the duplex such as which will exist due tobasepair mismatches between the control and sample strands. Forinstance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybridstreated with S₁ nuclease to enzymatically digesting the mismatchedregions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can betreated with hydroxylamine or osmium tetroxide and with piperidine inorder to digest mismatched regions. After digestion of the mismatchedregions, the resulting material is then separated by size on denaturingpolyacrylamide gels to determine the site of mutation. See, e.g.,Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, etal., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the controlDNA or RNA can be labeled for detection.

[0654] In still another embodiment, the mismatch cleavage reactionemploys one or more proteins that recognize mismatched base pairs indouble-stranded DNA (so called “DNA mismatch repair” enzymes) in definedsystems for detecting and mapping point mutations in NOVX cDNAs obtainedfrom samples of cells. For example, the mutY enzyme of E. coli cleaves Aat G/A mismatches and the thymidine DNA glycosylase from HeLa cellscleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994.Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, aprobe based on an NOVX sequence, e.g., a wild-type NOVX sequence, ishybridized to a cDNA or other DNA product from a test cell(s). Theduplex is treated with a DNA mismatch repair enzyme, and the cleavageproducts, if any, can be detected from electrophoresis protocols or thelike. See, e.g., U.S. Pat. No. 5,459,039. In other embodiments,alterations in electrophoretic mobility will be used to identifymutations in NOVX genes. For example, single strand conformationpolymorphism (SSCP) may be used to detect differences in electrophoreticmobility between mutant and wild type nucleic acids. See, e.g., Orita,et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat.Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79.Single-stranded DNA fragments of sample and control NOVX nucleic acidswill be denatured and allowed to renature. The secondary structure ofsingle-stranded nucleic acids varies according to sequence, theresulting alteration in electrophoretic mobility enables the detectionof even a single base change. The DNA fragments may be labeled ordetected with labeled probes. The sensitivity of the assay may beenhanced by using RNA (rather than DNA), in which the secondarystructure is more sensitive to a change in sequence. In one embodiment,the subject method utilizes heteroduplex analysis to separate doublestranded heteroduplex molecules on the basis of changes inelectrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet.7: 5.

[0655] In yet another embodiment, the movement of mutant or wild-typefragments in polyacrylamide gels containing a gradient of denaturant isassayed using denaturing gradient gel electrophoresis (DGGE). See, e.g.,Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method ofanalysis, DNA will be modified to insure that it does not completelydenature, for example by adding a GC clamp of approximately 40 bp ofhigh-melting GC-rich DNA by PCR. In a further embodiment, a temperaturegradient is used in place of a denaturing gradient to identifydifferences in the mobility of control and sample DNA. See, e.g.,Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.

[0656] Examples of other techniques for detecting point mutationsinclude, but are not limited to, selective oligonucleotidehybridization, selective amplification, or selective primer extension.For example, oligonucleotide primers may be prepared in which the knownmutation is placed centrally and then hybridized to target DNA underconditions that permit hybridization only if a perfect match is found.See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989.Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specificoligonucleotides are hybridized to PCR amplified target DNA or a numberof different mutations when the oligonucleotides are attached to thehybridizing membrane and hybridized with labeled target DNA.

[0657] Alternatively, allele specific amplification technology thatdepends on selective PCR amplification may be used in conjunction withthe instant invention. Oligonucleotides used as primers for specificamplification may carry the mutation of interest in the center of themolecule (so that amplification depends on differential hybridization;see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or atthe extreme 3′-terminus of one primer where, under appropriateconditions, mismatch can prevent, or reduce polymerase extension (see,e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirableto introduce a novel restriction site in the region of the mutation tocreate cleavage-based detection. See, e.g., Gasparini, et al., 1992.Mol. Cell Probes 6: 1. It is anticipated that in certain embodimentsamplification may also be performed using Taq ligase for amplification.See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In suchcases, ligation will occur only if there is a perfect match at the3′-terminus of the 5′ sequence, making it possible to detect thepresence of a known mutation at a specific site by looking for thepresence or absence of amplification. The methods described herein maybe performed, for example, by utilizing pre-packaged diagnostic kitscomprising at least one probe nucleic acid or antibody reagent describedherein, which may be conveniently used, e.g., in clinical settings todiagnose patients exhibiting symptoms or family history of a disease orillness involving an NOVX gene.

[0658] Furthermore, any cell type or tissue, preferably peripheral bloodleukocytes, in which NOVX is expressed may be utilized in the prognosticassays described herein. However, any biological sample containingnucleated cells may be used, including, for example, buccal mucosalcells.

[0659] Pharmacogenomics

[0660] Agents, or modulators that have a stimulatory or inhibitoryeffect on NOVX activity (e.g., NOVX gene expression), as identified by ascreening assay described herein can be administered to individuals totreat (prophylactically or therapeutically) disorders (The disordersinclude metabolic disorders, diabetes, obesity, infectious disease,anorexia, cancer-associated cachexia, cancer, neurodegenerativedisorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders,and hematopoietic disorders, and the various dyslipidemias, metabolicdisturbances associated with obesity, the metabolic syndrome X andwasting disorders associated with chronic diseases and various cancers.)In conjunction with such treatment, the pharmacogenomics (i.e., thestudy of the relationship between an individual's genotype and thatindividual's response to a foreign compound or drug) of the individualmay be considered. Differences in metabolism of therapeutics can lead tosevere toxicity or therapeutic failure by altering the relation betweendose and blood concentration of the pharmacologically active drug. Thus,the pharmacogenomics of the individual permits the selection ofeffective agents (e.g., drugs) for prophylactic or therapeutictreatments based on a consideration of the individual's genotype. Suchpharmacogenomics can further be used to determine appropriate dosagesand therapeutic regimens. Accordingly, the activity of NOVX protein,expression of NOVX nucleic acid, or mutation content of NOVX genes in anindividual can be determined to thereby select appropriate agent(s) fortherapeutic or prophylactic treatment of the individual.

[0661] Pharmacogenomics deals with clinically significant hereditaryvariations in the response to drugs due to altered drug disposition andabnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin.Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43:254-266. In general, two types of pharmacogenetic conditions can bedifferentiated. Genetic conditions transmitted as a single factoraltering the way drugs act on the body (altered drug action) or geneticconditions transmitted as single factors altering the way the body actson drugs (altered drug metabolism). These pharmacogenetic conditions canoccur either as rare defects or as polymorphisms. For example,glucose-6-phosphate dehydrogenase (G6PD) deficiency is a commoninherited enzymopathy in which the main clinical complication ishemolysis after ingestion of oxidant drugs (anti-malarials,sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0662] As an illustrative embodiment, the activity of drug metabolizingenzymes is a major determinant of both the intensity and duration ofdrug action. The discovery of genetic polymorphisms of drug metabolizingenzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymesCYP2D6 and CYP2C19) has provided an explanation as to why some patientsdo not obtain the expected drug effects or show exaggerated drugresponse and serious toxicity after taking the standard and safe dose ofa drug. These polymorphisms are expressed in two phenotypes in thepopulation, the extensive metabolizer (EM) and poor metabolizer (PM).The prevalence of PM is different among different populations. Forexample, the gene coding for CYP2D6 is highly polymorphic and severalmutations have been identified in PM, which all lead to the absence offunctional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quitefrequently experience exaggerated drug response and side effects whenthey receive standard doses. If a metabolite is the active therapeuticmoiety, PM show no therapeutic response, as demonstrated for theanalgesic effect of codeine mediated by its CYP2D6-formed metabolitemorphine. At the other extreme are the so called ultra-rapidmetabolizers who do not respond to standard doses. Recently, themolecular basis of ultra-rapid metabolism has been identified to be dueto CYP2D6 gene amplification.

[0663] Thus, the activity of NOVX protein, expression of NOVX nucleicacid, or mutation content of NOVX genes in an individual can bedetermined to thereby select appropriate agent(s) for therapeutic orprophylactic treatment of the individual. In addition, pharmacogeneticstudies can be used to apply genotyping of polymorphic alleles encodingdrug-metabolizing enzymes to the identification of an individual's drugresponsiveness phenotype. This knowledge, when applied to dosing or drugselection, can avoid adverse reactions or therapeutic failure and thusenhance therapeutic or prophylactic efficiency when treating a subjectwith an NOVX modulator, such as a modulator identified by one of theexemplary screening assays described herein.

[0664] Monitoring of Effects During Clinical Trials

[0665] Monitoring the influence of agents (e.g., drugs, compounds) onthe expression or activity of NOVX (e.g., the ability to modulateaberrant cell proliferation and/or differentiation) can be applied notonly in basic drug screening, but also in clinical trials. For example,the effectiveness of an agent determined by a screening assay asdescribed herein to increase NOVX gene expression, protein levels, orupregulate NOVX activity, can be monitored in clinical trails ofsubjects exhibiting decreased NOVX gene expression, protein levels, ordownregulated NOVX activity. Alternatively, the effectiveness of anagent determined by a screening assay to decrease NOVX gene expression,protein levels, or downregulate NOVX activity, can be monitored inclinical trails of subjects exhibiting increased NOVX gene expression,protein levels, or upregulated NOVX activity. In such clinical trials,the expression or activity of NOVX and, preferably, other genes thathave been implicated in, for example, a cellular proliferation or immunedisorder can be used as a “read out” or markers of the immuneresponsiveness of a particular cell.

[0666] By way of example, and not of limitation, genes, including NOVX,that are modulated in cells by treatment with an agent (e.g., compound,drug or small molecule) that modulates NOVX activity (e.g., identifiedin a screening assay as described herein) can be identified. Thus, tostudy the effect of agents on cellular proliferation disorders, forexample, in a clinical trial, cells can be isolated and RNA prepared andanalyzed for the levels of expression of NOVX and other genes implicatedin the disorder. The levels of gene expression (i.e., a gene expressionpattern) can be quantified by Northern blot analysis or RT-PCR, asdescribed herein, or alternatively by measuring the amount of proteinproduced, by one of the methods as described herein, or by measuring thelevels of activity of NOVX or other genes. In this manner, the geneexpression pattern can serve as a marker, indicative of thephysiological response of the cells to the agent. Accordingly, thisresponse state may be determined before, and at various points during,treatment of the individual with the agent.

[0667] In one embodiment, the invention provides a method for monitoringthe effectiveness of treatment of a subject with an agent (e.g., anagonist, antagonist, protein, peptide, peptidomimetic, nucleic acid,small molecule, or other drug candidate identified by the screeningassays described herein) comprising the steps of (i) obtaining apre-administration sample from a subject prior to administration of theagent; (ii) detecting the level of expression of an NOVX protein, mRNA,or genomic DNA in the preadministration sample; (iii) obtaining one ormore post-administration samples from the subject; (iv) detecting thelevel of expression or activity of the NOVX protein, mRNA, or genomicDNA in the post-administration samples; (v) comparing the level ofexpression or activity of the NOVX protein, mRNA, or genomic DNA in thepre-administration sample with the NOVX protein, mRNA, or genomic DNA inthe post administration sample or samples; and (vi) altering theadministration of the agent to the subject accordingly. For example,increased administration of the agent may be desirable to increase theexpression or activity of NOVX to higher levels than detected, i.e., toincrease the effectiveness of the agent. Alternatively, decreasedadministration of the agent may be desirable to decrease expression oractivity of NOVX to lower levels than detected, i.e., to decrease theeffectiveness of the agent.

[0668] Methods of Treatment

[0669] The invention provides for both prophylactic and therapeuticmethods of treating a subject at risk of (or susceptible to) a disorderor having a disorder associated with aberrant NOVX expression oractivity. The disorders include cardiomyopathy, atherosclerosis,hypertension, congenital heart defects, aortic stenosis, atrial septaldefect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus,pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD),valve diseases, tuberous sclerosis, scleroderma, obesity,transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia,prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer,fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenicpurpura, immunodeficiencies, graft versus host disease, AIDS, bronchialasthma, Crohn's disease; multiple sclerosis, treatment of AlbrightHereditary Ostoeodystrophy, and other diseases, disorders and conditionsof the like.

[0670] These methods of treatment will be discussed more fully, below.

[0671] Disease and Disorders

[0672] Diseases and disorders that are characterized by increased(relative to a subject not suffering from the disease or disorder)levels or biological activity may be treated with Therapeutics thatantagonize (i.e., reduce or inhibit) activity. Therapeutics thatantagonize activity may be administered in a therapeutic or prophylacticmanner. Therapeutics that may be utilized include, but are not limitedto: (i) an aforementioned peptide, or analogs, derivatives, fragments orhomologs thereof; (ii) antibodies to an aforementioned peptide; (iii)nucleic acids encoding an aforementioned peptide; (iv) administration ofantisense nucleic acid and nucleic acids that are “dysfunctional” (ie.,due to a heterologous insertion within the coding sequences of codingsequences to an aforementioned peptide) that are utilized to “knockout”endogenous function of an aforementioned peptide by homologousrecombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or(v) modulators (i.e., inhibitors, agonists and antagonists, includingadditional peptide mimetic of the invention or antibodies specific to apeptide of the invention) that alter the interaction between anaforementioned peptide and its binding partner.

[0673] Diseases and disorders that are characterized by decreased(relative to a subject not suffering from the disease or disorder)levels or biological activity may be treated with Therapeutics thatincrease (i.e., are agonists to) activity. Therapeutics that upregulateactivity may be administered in a therapeutic or prophylactic manner.Therapeutics that may be utilized include, but are not limited to, anaforementioned peptide, or analogs, derivatives, fragments or homologsthereof; or an agonist that increases bioavailability.

[0674] Increased or decreased levels can be readily detected byquantifying peptide and/or RNA, by obtaining a patient tissue sample(e.g., from biopsy tissue) and assaying it in vitro for RNA or peptidelevels, structure and/or activity of the expressed peptides (or mRNAs ofan aforementioned peptide). Methods that are well-known within the artinclude, but are not limited to, immunoassays (e.g., by Western blotanalysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/orhybridization assays to detect expression of mRNAs (e.g., Northernassays, dot blots, in situ hybridization, and the like).

[0675] Prophylactic Methods

[0676] In one aspect, the invention provides a method for preventing, ina subject, a disease or condition associated with an aberrant NOVXexpression or activity, by administering to the subject an agent thatmodulates NOVX expression or at least one NOVX activity. Subjects atrisk for a disease that is caused or contributed to by aberrant NOVXexpression or activity can be identified by, for example, any or acombination of diagnostic or prognostic assays as described herein.Administration of a prophylactic agent can occur prior to themanifestation of symptoms characteristic of the NOVX aberrancy, suchthat a disease or disorder is prevented or, alternatively, delayed inits progression. Depending upon the type of NOVX aberrancy, for example,an NOVX agonist or NOVX antagonist agent can be used for treating thesubject. The appropriate agent can be determined based on screeningassays described herein. The prophylactic methods of the invention arefurther discussed in the following subsections.

[0677] Therapeutic Methods

[0678] Another aspect of the invention pertains to methods of modulatingNOVX expression or activity for therapeutic purposes. The modulatorymethod of the invention involves contacting a cell with an agent thatmodulates one or more of the activities of NOVX protein activityassociated with the cell. An agent that modulates NOVX protein activitycan be an agent as described herein, such as a nucleic acid or aprotein, a naturally-occurring cognate ligand of an NOVX protein, apeptide, an NOVX peptidomimetic, or other small molecule. In oneembodiment, the agent stimulates one or more NOVX protein activity.Examples of such stimulatory agents include active NOVX protein and anucleic acid molecule encoding NOVX that has been introduced into thecell. In another embodiment, the agent inhibits one or more NOVX proteinactivity. Examples of such inhibitory agents include antisense NOVXnucleic acid molecules and anti-NOVX antibodies. These modulatorymethods can be performed in vitro (e.g., by culturing the cell with theagent) or, alternatively, in vivo (e.g., by administering the agent to asubject). As such, the invention provides methods of treating anindividual afflicted with a disease or disorder characterized byaberrant expression or activity of an NOVX protein or nucleic acidmolecule. In one embodiment, the method involves administering an agent(e.g., an agent identified by a screening assay described herein), orcombination of agents that modulates (e.g., up-regulates ordown-regulates) NOVX expression or activity. In another embodiment, themethod involves administering an NOVX protein or nucleic acid moleculeas therapy to compensate for reduced or aberrant NOVX expression oractivity.

[0679] Stimulation of NOVX activity is desirable in situations in whichNOVX is abnormally downregulated and/or in which increased NOVX activityis likely to have a beneficial effect. One example of such a situationis where a subject has a disorder characterized by aberrant cellproliferation and/or differentiation (e.g., cancer or immune associateddisorders). Another example of such a situation is where the subject hasa gestational disease (e.g., preclampsia).

[0680] Determination of the Biological Effect of the Therapeutic

[0681] In various embodiments of the invention, suitable in vitro or invivo assays are performed to determine the effect of a specificTherapeutic and whether its administration is indicated for treatment ofthe affected tissue.

[0682] In various specific embodiments, in vitro assays may be performedwith representative cells of the type(s) involved in the patient'sdisorder, to determine if a given Therapeutic exerts the desired effectupon the cell type(s). Compounds for use in therapy may be tested insuitable animal model systems including, but not limited to rats, mice,chicken, cows, monkeys, rabbits, and the like, prior to testing in humansubjects. Similarly, for in vivo testing, any of the animal model systemknown in the art may be used prior to administration to human subjects.

[0683] Prophylactic and Therapeutic Uses of the Compositions of theInvention

[0684] The NOVX nucleic acids and proteins of the invention are usefulin potential prophylactic and therapeutic applications implicated in avariety of disorders including, but not limited to: metabolic disorders,diabetes, obesity, infectious disease, anorexia, cancer-associatedcancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson'sDisorder, immune disorders, hematopoietic disorders, and the variousdyslipidemias, metabolic disturbances associated with obesity, themetabolic syndrome X and wasting disorders associated with chronicdiseases and various cancers.

[0685] As an example, a cDNA encoding the NOVX protein of the inventionmay be useful in gene therapy, and the protein may be useful whenadministered to a subject in need thereof. By way of non-limitingexample, the compositions of the invention will have efficacy fortreatment of patients suffering from: metabolic disorders, diabetes,obesity, infectious disease, anorexia, cancer-associated cachexia,cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson'sDisorder, immune disorders, hematopoietic disorders, and the variousdyslipidemias.

[0686] Both the novel nucleic acid encoding the NOVX protein, and theNOVX protein of the invention, or fragments thereof, may also be usefulin diagnostic applications, wherein the presence or amount of thenucleic acid or the protein are to be assessed. A further use could beas an anti-bacterial molecule (ie., some peptides have been found topossess anti-bacterial properties). These materials are further usefulin the generation of antibodies, which immunospecifically-bind to thenovel substances of the invention for use in therapeutic or diagnosticmethods.

[0687] The invention will be further described in the followingexamples, which do not limit the scope of the invention described in theclaims.

EXAMPLES Example 1 Identification of NOVX Clones

[0688] The novel NOVX target sequences identified in the presentinvention were subjected to the exon linking process to confirm thesequence. PCR primers were designed by starting at the most upstreamsequence available, for the forward primer, and at the most downstreamsequence available for the reverse primer. Table 21A shows the sequencesof the PCR primers used for obtaining different clones. In each case,the sequence was examined, walking inward from the respective terminitoward the coding sequence, until a suitable sequence that is eitherunique or highly selective was encountered, or, in the case of thereverse primer, until the stop codon was reached. Such primers weredesigned based on in silico predictions for the full length cDNA, part(one or more exons) of the DNA or protein sequence of the targetsequence, or by translated homology of the predicted exons to closelyrelated human sequences from other species. These primers were thenemployed in PCR amplification based on the following pool of humancDNAs: adrenal gland, bone marrow, brain—amygdala, brain—cerebellum,brain—hippocampus, brain—substantia nigra, brain—thalamus, brain—whole,fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney,lymphoma—Raji, mammary gland, pancreas, pituitary gland, placenta,prostate, salivary gland, skeletal muscle, small intestine, spinal cord,spleen, stomach, testis, thyroid, trachea, uterus. Usually the resultingamplicons were gel purified, cloned and sequenced to high redundancy.The PCR product derived from exon linking was cloned into the pCR2.1vector from Invitrogen. The resulting bacterial clone has an insertcovering the entire open reading frame cloned into the pCR2.1 vector.The resulting sequences from all clones were assembled with themselves,with other fragments in CuraGen Corporation's database and with publicESTs. Fragments and ESTs were included as components for an assemblywhen the extent of their identity with another component of the assemblywas at least 95% over 50 bp. In addition, sequence traces were evaluatedmanually and edited for corrections if appropriate. These proceduresprovide the sequence reported herein. TABLE 21A PCR Primers for ExonLinking NOVX SEQ SEQ Clone Primer 1 (5′-3′) ID Primer 2 (5′-3′) ID  3GTAAATTGGAAGAGTTTGTTCAAGGGAA 242 CTTGGAAATCCATCTTTCATTAAGTGAGC 243  9CTATCTGCCAATTTTCATTGTGGACAG 244 TTCGAATTAAGGTTCCAAGGCTATGAG 245 12bCGGGAAGACTCGCCAGCAC 246 AAAGCCTTTTATGGGTCTTTGAATTTATTG 247 14bTGCTGAGGGTGCATTTATGTTTCAG 248 CCACACGTGGATAATCAAGAGTTGAC 249 16bGCGGCGGCCATGGGAGATA 250 AGGAAGGGGAAGCGTCCTCAGTATTC 251 16cGCGGCGGCCATGGGAGATA 252 AGGAAGGGGAAGCGTCCTCAGTATTC 253 17AGCACGCACTTGCCCAGAGCTATC 254 CCTATGGCTGAAGGCGGAGGT 255 18CTGGGTCTCCCCTCCCAC 256 GTTTATTCTGAGCACCGGGAA 257 20 AGGCCTGCAGGTGGGTGTC258 CTGCAGGCTCCTACAGCTACTGCC 259

Example 2 Quantitative Expression Analysis of Clones in Various Cellsand Tissues

[0689] The quantitative expression of various clones was assessed usingmicrotiter plates containing RNA samples from a variety of normal andpathology-derived cells, cell lines and tissues using real timequantitative PCR (RTQ PCR). RTQ PCR was performed on an AppliedBiosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence DetectionSystem. Various collections of samples are assembled on the plates, andreferred to as Panel 1 (containing normal tissues and cancer celllines), Panel 2 (containing samples derived from tissues from normal andcancer sources), Panel 3 (containing cancer cell lines), Panel 4(containing cells and cell lines from normal tissues and cells relatedto inflammatory conditions), Panel 5D/5I (containing human tissues andcell lines with an emphasis on metabolic diseases),AI_comprehensive_panel (containing normal tissue and samples fromautoimmune diseases), Panel CNSD.01 (containing central nervous systemsamples from normal and diseased brains) and CNS_neurodegeneration_panel(containing samples from normal and Alzheimer's diseased brains).

[0690] RNA integrity from all samples is controlled for quality byvisual assessment of agarose gel electropherograms using 28S and 18Sribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s) and the absence of low molecular weight RNAs that would beindicative of degradation products. Samples are controlled againstgenomic DNA contamination by RTQ PCR reactions run in the absence ofreverse transcriptase using probe and primer sets designed to amplifyacross the span of a single exon.

[0691] First, the RNA samples were normalized to reference nucleic acidssuch as constitutively expressed genes (for example, β-actin and GAPDH).Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCRusing One Step RT-PCR Master Mix Reagents (Applied Biosystems; CatalogNo. 4309169) and gene-specific primers according to the manufacturer'sinstructions.

[0692] In other cases, non-normalized RNA samples were converted tosingle strand cDNA (sscDNA) using Superscript II (InvitrogenCorporation; Catalog No. 18064-147) and random hexamers according to themanufacturer's instructions. Reactions containing up to 10 ug of totalRNA were performed in a volume of 20 μl and incubated for 60 minutes at42° C. This reaction can be scaled up to 50 μg of total RNA in a finalvolume of 100 μl. sscDNA samples are then normalized to referencenucleic acids as described previously, using 1×TaqMan® Universal Mastermix (Applied Biosystems; catalog No. 4324020), following themanufacturer's instructions.

[0693] Probes and primers were designed for each assay according toApplied Biosystems Primer Express Software package (version I for AppleComputer's Macintosh Power PC) or a similar algorithm using the targetsequence as input. Default settings were used for reaction conditionsand the following parameters were set before selecting primers: primerconcentration=250 nM, primer melting temperature (Tm) range=58°-60° C.,primer optimal Tm=59° C., maximum primer difference =2° C., probe doesnot have 5′G, probe Tm must be 10° C. greater than primer Tm, ampliconsize 75 bp to 100 bp. The probes and primers selected (see below) weresynthesized by Synthegen (Houston, Tex., USA). Probes were doublepurified by HPLC to remove uncoupled dye and evaluated by massspectroscopy to verify coupling of reporter and quencher dyes to the 5′and 3′ ends of the probe, respectively. Their final concentrations were:forward and reverse primers, 900 nM each, and probe, 200 nM.

[0694] PCR conditions: When working with RNA samples, normalized RNAfrom each tissue and each cell line was spotted in each well of either a96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktailsincluded either a single gene specific probe and primers set, or twomultiplexed probe and primers sets (a set specific for the target cloneand another gene-specific set multiplexed with the target probe). PCRreactions were set up using TaqMan® One-Step RT-PCR Master Mix (AppliedBiosystems, Catalog No. 4313803) following manufacturer's instructions.Reverse transcription was performed at 48° C. for 30 minutes followed byamplification/PCR cycles as follows: 95° C. 10 min, then 40 cycles of95° C. for 15 seconds, 60° C. for 1 minute. Results were recorded as CTvalues (cycle at which a given sample crosses a threshold level offluorescence) using a log scale, with the difference in RNAconcentration between a given sample and the sample with the lowest CTvalue being represented as 2 to the power of delta CT. The percentrelative expression is then obtained by taking the reciprocal of thisRNA difference and multiplying by 100.

[0695] When working with sscDNA samples, normalized sscDNA was used asdescribed previously for RNA samples. PCR reactions containing one ortwo sets of probe and primers were set up as described previously, using1×TaqMan® Universal Master mix (Applied Biosystems; catalog No.4324020), following the manufacturer's instructions. PCR amplificationwas performed as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15seconds, 60° C. for 1 minute. Results were analyzed and processed asdescribed previously.

[0696] Panels 1, 1.1, 1.2, and 1.3D

[0697] The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 controlwells (genomic DNA control and chemistry control) and 94 wellscontaining cDNA from various samples. The samples in these panels arebroken into 2 classes: samples derived from cultured cell lines andsamples derived from primary normal tissues. The cell lines are derivedfrom cancers of the following types: lung cancer, breast cancer,melanoma, colon cancer, prostate cancer, CNS cancer, squamous cellcarcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancerand pancreatic cancer. Cell lines used in these panels are widelyavailable through the American Type Culture Collection (ATCC), arepository for cultured cell lines, and were cultured using theconditions recommended by the ATCC. The normal tissues found on thesepanels are comprised of samples derived from all major organ systemsfrom single adult individuals or fetuses. These samples are derived fromthe following organs: adult skeletal muscle, fetal skeletal muscle,adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetalliver, adult lung, fetal lung, various regions of the brain, the spleen,bone marrow, lymph node, pancreas, salivary gland, pituitary gland,adrenal gland, spinal cord, thymus, stomach, small intestine, colon,bladder, trachea, breast, ovary, uterus, placenta, prostate, testis andadipose.

[0698] In the results for Panels 1, 1.1, 1.2 and 1.3D, the followingabbreviations are used:

[0699] ca.=carcinoma,

[0700] *=established from metastasis,

[0701] met=metastasis,

[0702] s cell var=small cell variant,

[0703] non-s=non-sm=non-small,

[0704] squam=squamous,

[0705] pl.eff=pl effusion=pleural effusion,

[0706] glio=glioma,

[0707] astro=astrocytoma, and

[0708] neuro=neuroblastoma.

[0709] General_screening_panel_v1.4

[0710] The plates for Panel 1.4 include 2 control wells (genomic DNAcontrol and chemistry control) and 94 wells containing cDNA from varioussamples. The samples in Panel 1.4 are broken into 2 classes: samplesderived from cultured cell lines and samples derived from primary normaltissues. The cell lines are derived from cancers of the following types:lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNScancer, squamous cell carcinoma, ovarian cancer, liver cancer, renalcancer, gastric cancer and pancreatic cancer. Cell lines used in Panel1.4 are widely available through the American Type Culture Collection(ATCC), a repository for cultured cell lines, and were cultured usingthe conditions recommended by the ATCC. The normal tissues found onPanel 1.4 are comprised of pools of samples derived from all major organsystems from 2 to 5 different adult individuals or fetuses. Thesesamples are derived from the following organs: adult skeletal muscle,fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetalkidney, adult liver, fetal liver, adult lung, fetal lung, variousregions of the brain, the spleen, bone marrow, lymph node, pancreas,salivary gland, pituitary gland, adrenal gland, spinal cord, thymus,stomach, small intestine, colon, bladder, trachea, breast, ovary,uterus, placenta, prostate, testis and adipose. Abbreviations are asdescribed for Panels 1, 1.1, 1.2, and 1.3D.

[0711] Panels 2D and 2.2

[0712] The plates for Panels 2D and 2.2 generally include 2 controlwells and 94 test samples composed of RNA or cDNA isolated from humantissue procured by surgeons working in close cooperation with theNational Cancer Institute's Cooperative Human Tissue Network (CHTN) orthe National Disease Research Initiative (NDR1). The tissues are derivedfrom human malignancies and in cases where indicated many malignanttissues have “matched margins” obtained from noncancerous tissue justadjacent to the tumor. These are termed normal adjacent tissues and aredenoted “NAT” in the results below. The tumor tissue and the “matchedmargins” are evaluated by two independent pathologists (the surgicalpathologists and again by a pathologist at NDRI or CHTN). This analysisprovides a gross histopathological assessment of tumor differentiationgrade. Moreover, most samples include the original surgical pathologyreport that provides information regarding the clinical stage of thepatient. These matched margins are taken from the tissue surrounding(i.e. immediately proximal) to the zone of surgery (designated “NAT”,for normal adjacent tissue, in Table RR). In addition, RNA and cDNAsamples were obtained from various human tissues derived from autopsiesperformed on elderly people or sudden death victims (accidents, etc.).These tissues were ascertained to be free of disease and were purchasedfrom various commercial sources such as Clontech (Palo Alto, Calif.),Research Genetics, and Invitrogen.

[0713] Panel 3D

[0714] The plates of Panel 3D are comprised of 94 cDNA samples and twocontrol samples. Specifically, 92 of these samples are derived fromcultured human cancer cell lines, 2 samples of human primary cerebellartissue and 2 controls. The human cell lines are generally obtained fromATCC (American Type Culture Collection), NCI or the German tumor cellbank and fall into the following tissue groups: Squamous cell carcinomaof the tongue, breast cancer, prostate cancer, melanoma, epidermoidcarcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidneycancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon,lung and CNS cancer cell lines. In addition, there are two independentsamples of cerebellum. These cells are all cultured under standardrecommended conditions and RNA extracted using the standard procedures.The cell lines in panel 3D and 1.3D are of the most common cell linesused in the scientific literature.

[0715] Panels 4D, 4R, and 4.1D

[0716] Panel 4 includes samples on a 96 well plate (2 control wells, 94test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D)isolated from various human cell lines or tissues related toinflammatory conditions. Total RNA from control normal tissues such ascolon and lung (Stratagene, La Jolla, Calif.) and thymus and kidney(Clontech) was employed. Total RNA from liver tissue from cirrhosispatients and kidney from lupus patients was obtained from BioChain(Biochain Institute, Inc., Hayward, Calif.). Intestinal tissue for RNApreparation from patients diagnosed as having Crohn's disease andulcerative colitis was obtained from the National Disease ResearchInterchange (NDRI) (Philadelphia, Pa.).

[0717] Astrocytes, lung fibroblasts, dermal fibroblasts, coronary arterysmooth muscle cells, small airway epithelium, bronchial epithelium,microvascular dermal endothelial cells, microvascular lung endothelialcells, human pulmonary aortic endothelial cells, human umbilical veinendothelial cells were all purchased from Clonetics (Walkersville, Md.)and grown in the media supplied for these cell types by Clonetics. Theseprimary cell types were activated with various cytokines or combinationsof cytokines for 6 and/or 12-14 hours, as indicated. The followingcytokines were used; IL-1 beta at approximately 1-5 ng/ml, TNF alpha atapproximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 atapproximately 5-10 ng/ml. Endothelial cells were sometimes starved forvarious times by culture in the basal media from Clonetics with 0.1%serum.

[0718] Mononuclear cells were prepared from blood of employees atCuraGen Corporation, using Ficoll. LAK cells were prepared from thesecells by culture in DMEM 5% FCS (Hyclone), 100 μM non essential aminoacids (Gibco/Life Technologies, Rockville, Md.), 1 mM sodium pyruvate(Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) andInterleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and 1-2 μg/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at20-50 ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases,mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone),100 μM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) with PHA(phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml.Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR(mixed lymphocyte reaction) samples were obtained by taking blood fromtwo donors, isolating the mononuclear cells using Ficoll and mixing theisolated mononuclear cells 1:1 at a final concentration of approximately2×10⁶cells/ml in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids(Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol (5.5×10⁻⁵M)(Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samples takenat various time points ranging from 1-7 days for RNA preparation.

[0719] Monocytes were isolated from mononuclear cells using CD14Miltenyi Beads, +ve VS selection columns and a Vario Magnet according tothe manufacturer's instructions. Monocytes were differentiated intodendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone,Logan, Utah), 100 μM non essential amino acids (Gibco), 1 mM sodiumpyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mM Hepes(Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages wereprepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone),100AM non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵M (Gibco), 110 mM Hepes (Gibco) and 10% AB HumanSerum or MCSF at approximately 50 ng/ml. Monocytes, macrophages anddendritic cells were stimulated for 6 and 12-14 hours withlipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were alsostimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10 μg/mlfor 6 and 12-14 hours.

[0720] CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolatedfrom mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positiveVS selection columns and a Vario Magnet according to the manufacturer'sinstructions. CD45RA and CD45RO CD4 lymphocytes were isolated bydepleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8,CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beadswere then used to isolate the CD45RO CD4 lymphocytes with the remainingcells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 μM non essentialamino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol5.5×10⁻⁵M (Gibco), and 10 mM Hepes (Gibco) and plated at 10⁶cells/mlonto Falcon 6 well tissue culture plates that had been coated overnightwith 0.5 μg/ml anti-CD28 (Pharmingen) and 3 ug/ml anti-CD3 (OKT3, ATCC)in PBS. After 6 and 24 hours, the cells were harvested for RNApreparation. To prepare chronically activated CD8 lymphocytes, weactivated the isolated CD8 lymphocytes for 4 days on anti-CD28 andanti-CD3 coated plates and then harvested the cells and expanded them inDMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mMsodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mMHepes (Gibco) and IL-2. The expanded CD8 cells were then activated againwith plate bound anti-CD3 and anti-CD28 for 4 days and expanded asbefore. RNA was isolated 6 and 24 hours after the second activation andafter 4 days of the second expansion culture. The isolated NK cells werecultured in DMEM 5% FCS (Hyclone), 100 μM non essential amino acids(Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M(Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA wasprepared.

[0721] To obtain B cells, tonsils were procured from NDR1. The tonsilwas cut up with sterile dissecting scissors and then passed through asieve. Tonsil cells were then spun down and resupended at 10⁶cells/ml inDMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mMsodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mMHepes (Gibco). To activate the cells, we used PWM at 5 μg/ml oranti-CD40 (Pharmingen) at approximately 10 μg/ml and IL-4 at 5-10 ng/ml.Cells were harvested for RNA preparation at 24, 48 and 72 hours.

[0722] To prepare the primary and secondary Th1/Th2 and Tr1 cells,six-well Falcon plates were coated overnight with 10 μg/ml anti-CD28(Pharmingen) and 2 μg/ml OKT3 (ATCC), and then washed twice with PBS.Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, Md.)were cultured at 10⁵-10⁶cells/ml in DMEM 5% FCS (Hyclone), 100 μM nonessential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5 ng/ml) and anti-IL4 (1 μg/ml) were used to direct toTh1, while IL-4 (5 ng/ml) and anti-IFN gamma (1 μg/ml) were used todirect to Th2 and IL-10 at 5 ng/ml was used to direct to Tr1. After 4-5days, the activated Th1, Th2 and Tr1 lymphocytes were washed once inDMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 μM nonessential amino acids (Gibco), 1 mM sodium pyruvate (Gibco),mercaptoethanol 5.5×10⁻⁵M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1ng/ml). Following this, the activated Th1, Th2 and Tr1 lymphocytes werere-stimulated for 5 days with anti-CD28/OKT3 and cytokines as describedabove, but with the addition of anti-CD95L (1 μg/ml) to preventapoptosis. After 4-5 days, the Th1, Th2 and Tr1 lymphocytes were washedand then expanded again with IL-2 for 4-7 days. Activated Th1 and Th2lymphocytes were maintained in this way for a maximum of three cycles.RNA was prepared from primary and secondary Th1, Th2 and Tr1 after 6 and24 hours following the second and third activations with plate boundanti-CD3 and anti-CD28 mAbs and 4 days into the second and thirdexpansion cultures in Interleukin 2.

[0723] The following leukocyte cells lines were obtained from the ATCC:Ramos, EOL-1, KU-812. EOL cells were further differentiated by culturein 0.1 mM dbcAMP at 5×10⁵cells/ml for 8 days, changing the media every 3days and adjusting the cell concentration to 5×10⁵cells/ml. For theculture of these cells, we used DMEM or RPMI (as recommended by theATCC), with the addition of 5% FCS (Hyclone), 100 μM non essential aminoacids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M(Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cellsor cells activated with PMA at 10 ng/ml and ionomycin at 1 μg/ml for 6and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumorline NCI-H292 were also obtained from the ATCC. Both were cultured inDMEM 5% FCS (Hyclone), 100 μM non essential amino acids (Gibco), 1 mMsodium pyruvate (Gibco), mercaptoethanol 5.5×10⁻⁵M (Gibco), and 10 mMHepes (Gibco). CCD1106 cells were activated for 6 and 14 hours withapproximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.

[0724] For these cell lines and blood cells, RNA was prepared by lysingapproximately 10⁷cells/ml using Trizol (Gibco BRL). Briefly, {fraction(1/10)} volume of bromochloropropane (molecular Research Corporation)was added to the RNA sample, vortexed and after 10 minutes at roomtemperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor.The aqueous phase was removed and placed in a 15 ml Falcon Tube. Anequal volume of isopropanol was added and left at −20° C. overnight. Theprecipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34rotor and washed in 70% ethanol. The pellet was redissolved in 300 μl ofRNAse-free water and 35 μl buffer (Promega) 5 μl DTT, 7 μl RNAsin and 8μl DNAse were added. The tube was incubated at 37° C. for 30 minutes toremove contaminating genomic DNA, extracted once with phenol chloroformand re-precipitated with {fraction (1/10)} volume of 3M sodium acetateand 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAsefree water. RNA was stored at −80° C.

[0725] AI_comprehensive panel_v1.0

[0726] The plates for AI_comprehensive panel_v1.0 include two controlwells and 89 test samples comprised of cDNA isolated from surgical andpostmortem human tissues obtained from the Backus Hospital and Clinomics(Frederick, Md.). Total RNA was extracted from tissue samples from theBackus Hospital in the Facility at CuraGen. Total RNA from other tissueswas obtained from Clinomics.

[0727] Joint tissues including synovial fluid, synovium, bone andcartilage were obtained from patients undergoing total knee or hipreplacement surgery at the Backus Hospital. Tissue samples wereimmediately snap frozen in liquid nitrogen to ensure that isolated RNAwas of optimal quality and not degraded. Additional samples ofosteoarthritis and rheumatoid arthritis joint tissues were obtained fromClinomics. Normal control tissues were supplied by Clinomics and wereobtained during autopsy of trauma victims.

[0728] Surgical specimens of psoriatic tissues and adjacent matchedtissues were provided as total RNA by Clinomics. Two male and two femalepatients were selected between the ages of 25 and 47. None of thepatients were taking prescription drugs at the time samples wereisolated.

[0729] Surgical specimens of diseased colon from patients withulcerative colitis and Crohns disease and adjacent matched tissues wereobtained from Clinomics. Bowel tissue from three female and three maleCrohn's patients between the ages of 41-69 were used. Two patients werenot on prescription medication while the others were takingdexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue wasfrom three male and four female patients. Four of the patients weretaking lebvid and two were on phenobarbital.

[0730] Total RNA from post mortem lung tissue from trauma victims withno disease or with emphysema, asthma or COPD was purchased fromClinomics. Emphysema patients ranged in age from 40-70 and all weresmokers, this age range was chosen to focus on patients withcigarette-linked emphysema and to avoid those patients with alpha-ianti-trypsin deficiencies. Asthma patients ranged in age from 36-75, andexcluded smokers to prevent those patients that could also have COPD.COPD patients ranged in age from 35-80 and included both smokers andnon-smokers. Most patients were taking corticosteroids, andbronchodilators.

[0731] In the labels employed to identify tissues in theAI_comprehensive panel_(—)1.0 panel, the following abbreviations areused:

[0732] AI=Autoimmunity

[0733] Syn=Synovial

[0734] Normal=No apparent disease

[0735] Rep22/Rep20=individual patients

[0736] RA=Rheumatoid arthritis

[0737] Backus=From Backus Hospital

[0738] OA=Osteoarthritis

[0739] (SS) (BA) (MF)=Individual patients

[0740] Adj=Adjacent tissue

[0741] Match control=adjacent tissues

[0742] -M=Male

[0743] -F=Female

[0744] COPD=Chronic obstructive pulmonary disease

[0745] Panels 5D and 5I

[0746] The plates for Panel 5D and 5I include two control wells and avariety of cDNAs isolated from human tissues and cell lines with anemphasis on metabolic diseases. Metabolic tissues were obtained frompatients enrolled in the Gestational Diabetes study. Cells were obtainedduring different stages in the differentiation of adipocytes from humanmesenchymal stem cells. Human pancreatic islets were also obtained.

[0747] In the Gestational Diabetes study subjects are young (18-40years), otherwise healthy women with and without gestational diabetesundergoing routine (elective) Caesarean section. After delivery of theinfant, when the surgical incisions were being repaired/closed, theobstetrician removed a small sample.

[0748] Patient 2: Diabetic Hispanic, overweight, not on insulin

[0749] Patient 7-9: Nondiabetic Caucasian and obese (BMI>30)

[0750] Patient 10: Diabetic Hispanic, overweight, on insulin

[0751] Patient 11: Nondiabetic African American and overweight

[0752] Patient 12: Diabetic Hispanic on insulin

[0753] Adipocyte differentiation was induced in donor progenitor cellsobtained from Osirus (a division of Clonetics/BioWhittaker) intriplicate, except for Donor 3U which had only two replicates.Scientists at Clonetics isolated, grew and differentiated humanmesenchymal stem cells (HuMSCs) for CuraGen based on the publishedprotocol found in Mark F. Pittenger, et al., Multilineage Potential ofAdult Human Mesenchymal Stem Cells Science Apr. 2, 1999: 143-147.Clonetics provided Trizol lysates or frozen pellets suitable for mRNAisolation and ds cDNA production. A general description of each donor isas follows:

[0754] Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose

[0755] Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated

[0756] Donor 2 and 3 AD: Adipose, Adipose Differentiated

[0757] Human cell lines were generally obtained from ATCC (American TypeCulture Collection), NCI or the German tumor cell bank and fall into thefollowing tissue groups: kidney proximal convoluted tubule, uterinesmooth muscle cells, small intestine, liver HepG2 cancer cells, heartprimary stromal cells, and adrenal cortical adenoma cells. These cellsare all cultured under standard recommended conditions and RNA extractedusing the standard procedures. All samples were processed at CuraGen toproduce single stranded cDNA.

[0758] Panel 5I contains all samples previously described with theaddition of pancreatic islets from a 58 year old female patient obtainedfrom the Diabetes Research Institute at the University of Miami Schoolof Medicine. Islet tissue was processed to total RNA at an outsidesource and delivered to CuraGen for addition to panel 5I.

[0759] In the labels employed to identify tissues in the 5D and 5Ipanels, the following abbreviations are used:

[0760] GO Adipose=Greater Omentum Adipose

[0761] SK=Skeletal Muscle

[0762] UT=Uterus

[0763] PL=Placenta

[0764] AD=Adipose Differentiated

[0765] AM=Adipose Midway Differentiated

[0766] U=Undifferentiated Stem Cells

[0767] Panel CNSD.01

[0768] The plates for Panel CNSD.01 include two control wells and 94test samples comprised of cDNA isolated from postmortem human braintissue obtained from the Harvard Brain Tissue Resource Center. Brainsare removed from calvaria of donors between 4 and 24 hours after death,sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogenvapor. All brains are sectioned and examined by neuropathologists toconfirm diagnoses with clear associated neuropathology.

[0769] Disease diagnoses are taken from patient records. The panelcontains two brains from each of the following diagnoses: Alzheimer'sdisease, Parkinson's disease, Huntington's disease, ProgressiveSupemuclear Palsy, Depression, and “Normal controls”. Within each ofthese brains, the following regions are represented: cingulate gyrus,temporal pole, globus palladus, substantia nigra, Brodman Area 4(primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9(prefrontal cortex), and Brodman area 17 (occipital cortex). Not allbrain regions are represented in all cases; e.g., Huntington's diseaseis characterized in part by neurodegeneration in the globus palladus,thus this region is impossible to obtain from confirmed Huntington'scases. Likewise Parkinson's disease is characterized by degeneration ofthe substantia nigra making this region more difficult to obtain. Normalcontrol brains were examined for neuropathology and found to be free ofany pathology consistent with neurodegeneration.

[0770] In the labels employed to identify tissues in the CNS panel, thefollowing abbreviations are used:

[0771] PSP=Progressive supranuclear palsy

[0772] Sub Nigra=Substantia nigra

[0773] Glob Palladus=Globus palladus

[0774] Temp Pole=Temporal pole

[0775] Cing Gyr=Cingulate gyrus

[0776] BA 4=Brodman Area 4

[0777] Panel CNS_Neurodegeneration_V1.0

[0778] The plates for Panel CNS_Neurodegeneration_V1.0 include twocontrol wells and 47 test samples comprised of cDNA isolated frompostmortem human brain tissue obtained from the Harvard Brain TissueResource Center (McLean Hospital) and the Human Brain and Spinal FluidResource Center (VA Greater Los Angeles Healthcare System). Brains areremoved from calvaria of donors between 4 and 24 hours after death,sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogenvapor. All brains are sectioned and examined by neuropathologists toconfirm diagnoses with clear associated neuropathology.

[0779] Disease diagnoses are taken from patient records. The panelcontains six brains from Alzheimer's disease (AD) patients, and eightbrains from “Normal controls” who showed no evidence of dementia priorto death. The eight normal control brains are divided into twocategories: Controls with no dementia and no Alzheimer's like pathology(Controls) and controls with no dementia but evidence of severeAlzheimer's like pathology, (specifically senile plaque load rated aslevel 3 on a scale of 0-3; 0=no evidence of plaques, 3=severe AD senileplaque load). Within each of these brains, the following regions arerepresented: hippocampus, temporal cortex (Brodman Area 21), parietalcortex (Brodman area 7), and occipital cortex (Brodman area 17). Theseregions were chosen to encompass all levels of neurodegeneration in AD.The hippocampus is a region of early and severe neuronal loss in AD; thetemporal cortex is known to show neurodegeneration in AD after thehippocampus; the parietal cortex shows moderate neuronal death in thelate stages of the disease; the occipital cortex is spared in AD andtherefore acts as a “control” region within AD patients. Not all brainregions are represented in all cases.

[0780] In the labels employed to identify tissues in theCNS_Neurodegeneration_V1.0 panel, the following abbreviations are used:

[0781] AD=Alzheimer's disease brain; patient was demented and showedAD-like pathology upon autopsy

[0782] Control=Control brains; patient not demented, showing noneuropathology

[0783] Control (Path)=Control brains; pateint not demented but showingsever AD-like pathology

[0784] SupTemporal Ctx=Superior Temporal Cortex

[0785] Inf Temporal Ctx=Inferior Temporal Cortex

[0786] A. sggcdraft_ba186014_(—)20000730_da1: LYSOSOMAL ACID LIPASE(NOV1)

[0787] Expression of gene sggc_draft_ba186014_(—)20000730_da1 wasassessed using the primer-probe sets Ag1456, Ag2446, Ag2132, Ag2444,Ag1899 and Ag2059, described in Tables AA, AB, AC, AD, AE and AF.Results of the RTQ-PCR runs are shown in Tables AG, AH, AI, AJ and AK.TABLE AA Probe Name Ag1456 Primers Sequences Start Position SEQ ID NOForward 5′-tcctgaggtgtggatgaatact-3′ 91 260 ProbeTET-5′-catcatctacaatggctaccccagtga-3′-TAMRA 121 261 Reverse5′-ccatcttcagtggtgacttcat-3′ 153 262

[0788] TABLE AB Probe Name Ag2446 Primers Sequences Start Position SEQID NO Forward 5′-gaaacagtcggggaaacact-3′ 354 263 ProbeTET-5′-tggtcaagaagacacaaaacactctca-3′-TAMRA 374 264 Reverse5′-aaaccaaaggcccagaattt-3′ 413 265

[0789] TABLE AC Probe Name Ag2132 Primers Sequences Start Position SEQID NO Forward 5′-ggggaaatgacgctgataatat-3′ 858 266 ProbeTET-5′-cccctatatatgacctgactgccatg-3′-TAMRA 903 267 Reverse5′-cccaaatagcagtaggcacttt-3′ 929 268

[0790] TABLE AD Probe Name Ag2444 Primers Sequences Start Position SEQID NO Forward 5′-gaaacagtcggggaaacact-3′ 354 269 ProbeTET-5′-tggtcaagaagacacaaaacactctca-3′-TAMRA 374 270 Reverse5′-aaaccaaaggcccagaattt-3′ 413 271

[0791] TABLE AE Probe Name Ag1899 Primers Sequences Start Position SEQID NO Forward 5′-tcctgaggtgtggatgaatact-3′ 91 272 ProbeTET-5′-catcatctacaatggctaccccagtga-3′-TAMRA 122 273 Reverse5′-ccatcttcagtggtgacttcat-3′ 153 274

[0792] TABLE AF Probe Name Ag2059 Primers Sequences Start Position SEQID NO Forward 5′-ggggaaatgacgctgataatat-3′ 858 275 ProbeTET-5′-cccctatatatgacctgactgccatg-3′-TAMRA 903 276 Reverse5′-cccaaatagcagtaggcacttt-3′ 929 277

[0793] TABLE AG AI_comprehensive panel_v1.0 Rel. Exp. (%) Rel. Exp. (%)Ag1456, Run Ag1456, Run Tissue Name 224501612 Tissue Name 224501612110967 COPD-F 0.0 112427 Match Control 0.0 Psoriasis-F 110980 COPD-F 2.1112418 Psoriasis-M 0.0 110968 COPD-M 0.0 112723 Match Control 0.0Psoriasis-M 110977 COPD-M 0.0 112419 Psoriasis-M 0.0 110989 Emphysema-F2.6 112424 Match Control 0.0 Psoriasis-M 110992 Emphysema-F 0.0 112420Psoriasis-M 4.4 110993 Emphysema-F 0.0 112425 Match Control 0.0Psoriasis-M 110994 Emphysema-F 0.0 104689 (MF) OA 0.0 Bone-Backus 110995Emphysema-F 0.0 104690 (MF) Adj 3.0 “Normal” Bone-Backus 110996Emphysema-F 0.0 104691 (MF) OA 35.1 Synovium-Backus 110997 Asthma-M 5.0104692 (BA) OA 0.0 Cartilage-Backus 111001 Asthma-F 1.6 104694 (BA) OA3.2 Bone-Backus 111002 Asthma-F 2.5 104695 (BA) Adj 3.1 “Normal”Bone-Backus 111003 Atopic 0.0 104696 (BA) OA 20.9 Asthma-FSynovium-Backus 111004 Atopic 0.0 104700 (SS) OA Bone- 39.0 Asthma-FBackus 111005 Atopic 0.0 104701 (SS) Adj 3.3 Asthma-F “Normal”Bone-Backus 111006 Atopic 0.0 104702 (SS) OA 5.0 Asthma-FSynovium-Backus 111417 Allergy-M 0.0 117093 OA Cartilage 0.0 Rep7 112347Allergy-M 0.8 112672 OA Bone5 0.0 112349 Normal Lung-F 0.0 112673 OASynovium5 0.0 112357 Normal Lung-F 0.0 112674 OA Synovial 0.0 Fluidcells5 112354 Normal Lung-M 0.0 117100 OA Cartilage 0.0 Rep14 112374Crohns-F 2.4 112756 OA Bone9 0.0 112389 Match 100.0 112757 OA Synovium90.0 Control Crohns-F 112375 Crohns-F 0.0 112758 OA Synovial 1.3 FluidCells9 112732 Match 5.0 117125 RA Cartilage 0.0 Control Crohns-F Rep2112725 Crohns-M 1.5 113492 Bone2 RA 62.0 112387 Match 0.0 113493Synovium2 RA 8.7 Control Crohns-M 112378 Crohns-M 0.0 113494 Syn FluidCells RA 21.0 112390 Match 2.3 113499 Cartilage4 RA 20.6 ControlCrohns-M 112726 Crohns-M 0.0 113500 Bone4 RA 25.5 112731 Match 0.0113501 Synovium4 RA 15.3 Control Crohns-M 112380 Ulcer Col-F 0.0 113502Syn Fluid 8.5 Cells4 RA 112734 Match 52.5 113495 Cartilage3 RA 33.7Control Ulcer Col-F 112384 Ulcer Col-F 0.0 113496 Bone3 RA 33.7 112737Match 2.5 113497 Synovium3 RA 19.9 Control Ulcer Col-F 112386 UlcerCol-F 2.4 113498 Syn Fluid 37.6 Cells3 RA 112738 Match 3.3 117106 Normal0.0 Control Ulcer Col-F Cartilage Rep20 112381 Ulcer Col-M 0.0 113663Bone3 Normal 0.0 112735 Match 1.4 113664 Synovium3 0.9 Control UlcerCol-M Normal 112382 Ulcer Col-M 28.5 113665 Syn Fluid 0.0 Cells3 Normal112394 Match 0.0 117107 Normal 2.4 Control Ulcer Col-M Cartilage Rep22112383 Ulcer Col-M 0.0 113667 Bone4 Normal 0.0 112736 Match 74.2 113668Synovium4 0.0 Control Ulcer Col-M Normal 112423 Psoriasis-F 4.4 113669Syn Fluid 0.0 Cells4 Normal

[0794] TABLE AH Panel 1.2 Rel. Exp. (%) Ag1456, Rel. Exp. (%) Ag1456,Tissue Name Run 138374123 Tissue Name Run 138374123 Endothelial cells0.0 Renal ca. 786-0 0.0 Heart (Fetal) 0.6 Renal ca. A498 0.0 Pancreas0.0 Renal ca. RXF 393 0.0 Pancreatic ca. CAPAN 2 0.0 Renal ca. ACHN 0.0Adrenal Gland 10.7 Renal ca. UO-31 0.0 Thyroid 1.3 Renal ca. TK-10 0.0Salivary gland 3.2 Liver 4.1 Pituitary gland 0.3 Liver (fetal) 4.5 Brain(fetal) 0.6 Liver ca. 0.0 (hepatoblast) HepG2 Brain (whole) 0.0 Lung 5.6Brain (amygdala) 0.5 Lung (fetal) 1.2 Brain (cerebellum) 0.0 Lung ca.(small cell) 5.9 LX-1 Brain (hippocampus) 0.7 Lung ca. (small cell) 1.7NCI-H69 Brain (thalamus) 0.7 Lung ca. (s.cell var.) 0.0 SHP-77 CerebralCortex 0.0 Lung ca. (large 0.0 cell)NCI-H460 Spinal cord 2.1 Lung ca.(non-sm. 0.0 cell) A549 glio/astro U87-MG 0.0 Lung ca. (non-s.cell) 60.3NCI-H23 glio/astro U-118-MG 1.8 Lung ca. (non-s.cell) 0.0 HOP-62astrocytoma SW1783 0.0 Lung ca. (non-s.cl) 2.8 NCI-H522 neuro*; metSK-N-AS 0.0 Lung ca. (squam.) 0.0 SW 900 astrocytoma SF-539 0.0 Lung ca.(squam.) 0.0 NCI-H596 astrocytoma SNB-75 0.0 Mammary gland 0.0 gliomaSNB-19 0.0 Breast ca.* (pl.ef) 0.9 MCF-7 glioma U251 0.0 Breast ca.*(pl.ef) 0.0 MDA-MB-231 glioma SF-295 0.0 Breast ca.* (pl. ef) 0.0 T47DHeart 19.9 Breast ca. BT-549 0.0 Skeletal Muscle 8.2 Breast ca. MDA-N0.0 Bone marrow 100.0 Ovary 0.0 Thymus 0.6 Ovarian ca. OVCAR-3 0.0Spleen 12.3 Ovarian ca. OVCAR-4 0.0 Lymph node 0.9 Ovarian ca. OVCAR-51.4 Colorectal Tissue 1.9 Ovarian ca. OVCAR-8 0.0 Stomach 2.0 Ovarianca. IGROV-1 0.0 Small intestine 1.2 Ovarian ca. (ascites) 0.0 SK-OV-3Colon ca. SW480 0.5 Uterus 0.4 Colon ca.* SW620 3.1 Placenta 2.2 (SW480met) Colon ca. HT29 0.0 Prostate 1.4 Colon ca. HCT-116 0.0 Prostate ca.*(bone 0.0 met) PC-3 Colon ca. CaCo-2 0.5 Testis 0.0 Colon ca. Tissue 8.2Melanoma 0.0 (ODO3866) Hs688(A).T Colon ca. HCC-2998 0.0 Melanoma* (met)0.0 Hs688(B).T Gastric ca.* (liver 2.4 Melanoma UACC-62 0.0 met) NCI-N87Bladder 29.1 Melanoma M14 0.0 Trachea 0.6 Melanoma LOX 0.0 IMVI Kidney3.1 Melanoma* (met) 1.2 SK-MEL-5 Kidney (fetal) 2.5

[0795] TABLE AI Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag1456, Run Ag1456, Run Ag2132, Run Ag2444, Run TissueName 147644869 165529464 160164823 165629988 Liver 0.0 0.0 0.0 0.0adenocarcinoma Pancreas 0.0 0.0 0.0 1.9 Pancreatic ca. 0.0 0.0 0.0 0.0CAPAN 2 Adrenal gland 9.2 7.6 5.2 1.9 Thyroid 0.0 0.0 0.0 1.6 Salivarygland 0.0 0.0 0.0 0.4 Pituitary gland 0.0 0.0 0.0 0.6 Brain (fetal) 0.00.0 0.0 1.4 Brain (whole) 0.0 0.0 0.0 0.3 Brain (amygdala) 0.0 0.0 0.00.0 Brain (cerebellum) 0.0 0.0 0.0 0.0 Brain (hippocampus) 0.0 0.0 0.00.4 Brain (substantia 4.6 0.0 0.0 0.4 nigra) Brain (thalamus) 0.0 0.00.0 0.0 Cerebral Cortex 0.0 0.0 0.0 0.5 Spinal cord 0.0 10.4 3.5 1.2glio/astro U87-MG 0.0 0.0 0.0 0.0 glio/astro U-118-MG 12.4 0.0 10.7 8.5astrocytoma 0.0 0.0 0.0 0.0 SW1783 neuro*; met SK-N- 0.0 0.0 0.0 0.0 ASastrocytoma SF-539 0.0 0.0 0.0 0.0 astrocytoma SNB-75 0.0 0.0 0.0 2.5glioma SNB-19 0.0 0.0 0.0 0.0 glioma U251 0.0 0.0 0.0 0.6 glioma SF-2950.0 0.0 0.0 0.0 Heart (fetal) 5.8 0.0 0.0 0.0 Heart 0.0 0.0 0.0 0.5Skeletal muscle 0.0 0.0 0.0 0.3 (fetal) Skeletal muscle 0.0 6.2 5.0 0.6Bone marrow 100.0 100.0 66.4 0.0 Thymus 0.0 0.0 7.2 0.0 Spleen 11.4 8.821.2 0.0 Lymph node 5.0 7.4 0.0 1.3 Colorectal 0.0 0.0 0.0 0.3 Stomach0.0 0.0 0.0 0.9 Small intestine 0.0 0.0 0.0 0.4 Colon ca. SW480 0.0 0.00.0 0.0 Colon ca.* 0.0 0.0 0.0 0.0 SW620(SW480 met) Colon ca. HT29 0.00.0 0.0 1.1 Colon ca. HCT-116 0.0 0.0 0.0 0.0 Colon ca. CaCo-2 0.0 0.00.0 0.8 Colon ca. 10.8 17.3 23.2 0.6 tissue(ODO3866) Colon ca. HCC-29980.0 0.0 0.0 1.4 Gastric ca.* (liver 0.0 0.0 1.8 100.0 met) NCI-N87Bladder 0.0 6.7 0.0 1.5 Trachea 0.0 0.0 31.6 1.2 Kidney 0.0 0.0 0.0 0.6Kidney (fetal) 5.1 0.0 0.0 0.0 Renal ca. 786-0 0.0 0.0 0.0 0.0 Renal ca.A498 0.0 0.0 3.9 0.1 Renal ca. RXF 393 0.0 0.0 0.0 1.4 Renal ca. ACHN0.0 0.0 0.0 24.7 Renal ca. UO-31 0.0 0.0 0.0 0.0 Renal ca. TK-10 0.0 0.00.0 0.0 Liver 0.0 0.0 0.0 0.0 Liver (fetal) 3.7 0.0 0.0 0.0 Liver ca.0.0 0.0 0.0 0.0 (hepatoblast) HepG2 Lung 38.4 25.0 100.0 1.3 Lung(fetal) 18.9 5.7 15.1 0.0 Lung ca. (small cell) 11.7 0.0 0.0 0.3 LX-1Lung ca. (small cell) 0.0 0.0 0.0 2.3 NCI-H69 Lung ca. (s.cell var.) 0.00.0 0.0 0.0 SHP-77 Lung ca. (large 0.0 0.0 0.0 0.5 cell)NCI-H460 Lungca. (non-sm. 0.0 0.0 0.0 3.3 cell)A549 Lung ca. (non-s.cell) 38.2 17.910.2 21.5 NCI-H23 Lung ca. (non-s.cell) 0.0 0.0 0.0 0.0 HOP-62 Lung ca.(non-s.cl) 0.0 0.0 0.0 0.3 NCI-H522 Lung ca. (squam.) 0.0 0.0 0.0 2.2 SW900 Lung ca. (squam.) 0.0 0.0 0.0 0.5 NCI-H596 Mammary gland 0.0 0.0 0.00.6 Breast ca.* (pl.ef) 0.0 0.0 0.0 35.4 MCF-7 Breast ca.* (pl.ef) 0.00.0 0.0 0.0 MDA-MB-231 Breast ca.* (pl.ef) 0.0 0.0 0.0 5.6 T47D Breastca. BT-549 0.0 0.0 0.0 1.7 Breast ca. MDA-N 0.0 0.0 0.0 0.0 Ovary 0.00.0 0.0 2.3 Ovarian ca. 0.0 0.0 0.0 17.7 OVCAR-3 Ovarian ca. 0.0 0.0 0.017.1 OVCAR-4 Ovarian ca. 0.0 0.0 0.0 0.9 OVCAR-5 Ovarian ca. 0.0 0.0 0.04.4 OVCAR-8 Ovarian ca. IGROV-1 0.0 0.0 0.0 0.0 Ovarian ca.* 0.0 0.0 0.08.0 (ascites) SK-OV-3 Uterus 0.0 0.0 0.0 3.0 Placenta 5.3 0.0 16.5 0.0Prostate 0.0 0.0 0.0 0.0 Prostate ca.* (bone 0.0 0.0 0.0 32.8 met)PC-3Testis 5.3 0.0 0.0 1.3 Melanoma 0.0 0.0 0.0 0.0 Hs688(A).T Melanoma*(met) 0.0 0.0 0.0 0.0 Hs688(B).T Melanoma UACC- 0.0 0.0 0.0 0.5 62Melanoma M14 0.0 0.0 0.0 0.6 Melanoma LOX 0.0 0.0 0.0 0.0 IMVI Melanoma*(met) 0.0 0.0 0.0 0.0 SK-MEL-5 Adipose 27.0 14.3 10.7 4.0

[0796] TABLE AJ Panel 2D Rel. Rel. Rel. Rel. Rel. Rel. Exp. (%) Exp. (%)Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag1456, Ag1456, Ag1456, Ag1456,Ag1456, Ag1456, Tissue Run Run Run Tissue Run Run Run Name 147644930148059395 162599938 Name 147644930 148059395 162599938 Normal 13.2 2.16.3 Kidney 0.0 0.6 1.0 Colon Margin 8120608 CC Well to 5.5 2.4 2.6Kidney 1.0 0.8 0.8 Mod Diff Cancer (ODO3866) 8120613 CC Margin 2.1 3.22.3 Kidney 0.0 0.0 0.0 (ODO3866) Margin 8120614 CC Gr.2 0.6 0.0 1.7Kidney 17.9 13.8 15.0 rectosigmoid Cancer (ODO3868) 9010320 CC Margin0.0 0.0 0.8 Kidney 0.7 1.4 1.4 (ODO3868) Margin 9010321 CC Mod 1.8 2.93.5 Normal 0.0 0.0 0.0 Diff Uterus (ODO3920) CC Margin 0.5 1.2 2.6Uterus 1.2 0.5 2.1 (ODO3920) Cancer 064011 CC Gr.2 1.3 9.2 6.5 Normal0.0 0.6 0.7 ascend colon Thyroid (ODO3921) CC Margin 0.0 0.5 1.7 Thyroid0.0 1.3 2.8 (ODO3921) Cancer 064010 CC from 2.3 6.7 7.1 Thyroid 1.9 0.63.0 Partial Cancer Hepatectomy A302152 (ODO4309) Mets Liver 3.2 7.3 2.3Thyroid 0.0 0.0 1.9 Margin Margin (ODO4309) A302153 Colon mets 1.3 0.60.0 Normal 0.8 1.9 0.0 to lung Breast (OD04451- 01) Lung Margin 2.0 4.51.9 Breast 0.0 0.0 0.0 (OD04451- Cancer 02 (OD04566) Normal 0.0 0.0 0.0Breast 0.0 1.9 0.0 Prostate Cancer 6546-1 (OD04590- 01) Prostate 0.7 0.02.9 Breast 0.9 0.5 1.4 Cancer Cancer (OD04410) Mets (OD04590- 03)Prostate 0.6 0.0 0.0 Breast 1.1 0.6 1.7 Margin Cancer (OD04410)Metastasis (OD04655- 05) Prostate 0.6 0.0 0.0 Breast 0.0 0.7 0.0 CancerCancer (OD04720- 064006 01) Prostate 2.8 0.2 2.9 Breast 0.7 0.0 0.9Margin Cancer (OD04720- 1024 02) Normal 7.4 8.2 0.0 Breast 0.0 0.0 0.0Lung Cancer 061010 9100266 Lung Met to 6.1 2.0 5.8 Breast 0.7 0.0 0.0Muscle Margin (ODO4286) 9100265 Muscle 1.5 0.6 1.1 Breast 0.8 0.0 0.0Margin Cancer (ODO4286) A209073 Lung 9.9 7.3 4.1 Breast 0.0 0.0 0.0Malignant Margin Cancer A2090734 (OD03126) Lung Margin 33.9 28.1 27.0Normal 0.0 0.0 1.1 (OD03126) Liver Lung Cancer 13.3 11.2 13.0 Liver 1.40.0 0.0 (OD04404) Cancer 064003 Lung Margin 32.8 22.2 28.3 Liver 0.0 0.00.8 (OD04404) Cancer 1025 Lung Cancer 4.5 1.3 5.7 Liver 2.2 1.8 0.9(OD04565) Cancer 1026 Lung Margin 0.0 7.2 4.9 Liver 1.2 1.0 0.0(OD04565) Cancer 6004-T Lung Cancer 2.1 1.6 3.5 Liver 1.1 0.7 2.7(OD04237- Tissue 01) 6004-N Lung Margin 100.0 100.0 100.0 Liver 0.0 0.00.8 (OD04237- Cancer 02) 6005-T Ocular Mel 0.3 0.0 0.0 Liver 0.0 0.0 0.6Met to Liver Tissue (ODO4310) 6005-N Liver 1.9 0.6 0.7 Normal 3.9 1.88.4 Margin Bladder (ODO4310) Melanoma 0.5 0.0 0.0 Bladder 0.0 0.0 0.0Mets to Cancer Lung 1023 (OD04321) Lung Margin 22.8 27.5 24.5 Bladder3.3 5.2 1.7 (OD04321) Cancer A302173 Normal 0.0 0.6 1.6 Bladder 13.011.0 11.8 Kidney Cancer (OD04718- 01) Kidney Ca, 8.7 11.5 16.5 Bladder14.6 12.7 15.9 Nuclear Normal grade 2 Adjacent (OD04338) (OD04718- 03)Kidney 2.0 6.1 3.2 Normal 0.0 0.0 0.0 Margin Ovary (OD04338) Kidney Ca1.4 0.6 0.8 Ovarian 0.0 0.8 0.0 Nuclear Cancer grade 1/2 064008(OD04339) Kidney 0.0 0.5 2.6 Ovarian 2.9 2.3 6.0 Margin Cancer (OD04339)(OD04768- 07) Kidney Ca, 20.0 26.8 25.9 Ovary 16.7 20.9 12.9 Clear cellMargin type (OD04768- (OD04340) 08) Kidney 7.2 3.4 9.7 Normal 1.1 3.33.2 Margin Stomach (OD04340) Kidney Ca, 0.7 0.0 0.5 Gastric 0.0 0.0 0.0Nuclear Cancer grade 3 9060358 (OD04348) Kidney 1.2 1.4 1.8 Stomach 3.15.9 3.3 Margin Margin (OD04348) 9060359 Kidney 11.2 11.2 20.9 Gastric13.2 3.7 11.0 Cancer Cancer (OD04622- 9060395 01) Kidney 1.6 1.0 1.4Stomach 1.6 2.7 4.3 Margin Margin (OD04622- 9060394 03) Kidney 0.7 0.00.0 Gastric 19.1 7.4 9.8 Cancer Cancer (OD04450- 9060397 01) Kidney 0.01.4 3.2 Stomach 0.0 1.2 0.8 Margin Margin (OD04450- 9060396 03) Kidney0.0 0.0 0.0 Gastric 4.3 5.6 3.9 Cancer Cancer 8120607 064005

[0797] TABLE AK Panel 4D Rel. Rel. Rel. Rel. Rel. Rel. Exp. (%) Exp. (%)Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag1456, Ag1456, Ag1899, Ag2059,Ag2132, Ag2444, Run Run Run Run Run Run Tissue Name 139309823 144691235165870453 161426290 159366502 164320874 Secondary Th1 act 0.0 0.0 0.00.0 0.0 0.0 Secondary Th2 act 0.4 0.4 0.0 0.0 0.0 0.0 Secondary Tr1 act0.0 0.0 0.0 0.0 0.0 0.0 Secondary Th1 rest 0.0 0.0 0.3 0.0 0.0 0.0Secondary Th2 rest 6.1 4.8 2.4 0.8 2.7 0.0 Secondary Tr1 rest 0.4 0.00.3 0.0 1.4 0.0 Primary Th1 act 0.0 0.7 0.0 0.0 0.0 0.0 Primary Th2 act1.5 0.3 0.6 0.0 0.0 0.0 Primary Tr1 act 0.0 0.6 0.1 0.0 0.0 0.0 PrimaryTh1 rest 4.5 4.1 7.9 3.0 5.3 0.0 Pnimary Th2 rest 6.5 2.9 3.7 6.3 1.141.5 Primary Tr1 rest 2.7 3.5 1.6 2.5 1.0 0.0 CD45RA CD4 0.0 0.0 0.0 0.00.0 0.0 lymphocyte act CD45RO CD4 0.0 0.4 0.3 0.0 0.0 0.0 lymphocyte actCD8 lymphocyte 0.0 0.0 0.0 0.0 0.0 0.0 act Secondary CD8 0.5 0.0 0.2 0.00.0 0.0 lymphocyte rest Secondary CD8 0.6 0.0 0.0 0.0 0.0 0.0 lymphocyteact CD4 lymphocyte 3.1 1.1 1.4 5.1 0.0 0.0 none 2ry 4.3 5.9 4.7 2.1 3.50.0 Th1/Th2/Tr1_anti- CD95 CH11 LAK cells rest 0.5 1.1 0.5 0.0 0.0 0.0LAK cells IL-2 1.0 1.4 0.8 0.0 1.6 0.0 LAK cells IL- 1.0 0.9 0.2 0.0 0.00.0 2 + IL-12 LAK cells IL- 0.5 2.1 0.6 0.0 0.0 0.0 2 + IFN gamma LAKcells IL-2 + 1.0 0.4 0.4 0.0 0.0 0.0 IL-18 LAK cells 17.1 17.8 8.0 8.510.0 0.0 PMA/ionomycin NK Cells IL-2 rest 0.0 0.0 0.2 1.2 0.0 0.0 TwoWay MLR 3 0.0 0.0 0.0 1.5 0.0 38.7 day Two Way MLR 5 0.0 0.3 0.0 0.0 0.00.0 day Two Way MLR 7 0.0 0.5 0.0 0.0 0.0 0.0 day PBMC rest 20.3 22.218.4 6.7 14.0 100.0 PBMC PWM 0.5 0.0 0.0 0.0 1.3 45.7 PBMC PHA-L 0.0 1.00.2 0.0 0.0 0.0 Ramos (B cell) 36.1 48.6 21.0 0.0 7.2 44.1 none Ramos (Bcell) 100.0 87.1 16.6 44.1 27.9 46.7 ionomycin B lymphocytes 0.5 0.0 0.01.6 0.0 0.0 PWM B lymphocytes 0.5 0.0 0.0 0.0 0.0 0.0 CD40L and IL-4EOL-1 dbcAMP 0.0 0.0 0.2 0.0 0.0 0.0 EOL-1 dbcAMP 0.4 0.0 0.6 1.1 1.20.0 PMA/ionomycin Dendritic cells 5.6 4.7 4.3 3.7 8.4 0.0 none Dendriticcells LPS 3.0 1.8 2.3 3.7 1.8 30.1 Dendritic cells 2.6 3.2 2.0 4.7 0.00.0 anti-CD40 Monocytes rest 97.3 100.0 100.0 100.0 100.0 82.4 MonocytesLPS 34.2 34.4 20.3 15.8 19.3 32.5 Macrophages rest 5.1 5.5 3.0 4.0 1.30.0 Macrophages LPS 7.5 9.7 4.8 3.0 0.0 0.0 HUVEC none 0.0 0.0 0.0 0.00.0 0.0 HUVEC starved 0.0 0.0 0.0 0.0 0.0 0.0 HUVEC IL-1beta 0.0 0.0 0.00.0 0.0 0.0 HUVEC IFN 0.0 0.0 0.0 0.0 0.0 0.0 gamma HUVEC TNF 0.0 0.00.0 0.0 0.0 0.0 alpha + IFN gamma HUVEC TNF 0.0 0.0 0.0 0.0 0.0 0.0alpha + IL4 HUVEC IL-11 0.0 0.0 0.0 0.0 0.0 0.0 Lung 0.0 0.0 0.0 0.0 0.00.0 Microvascular EC none Lung 0.0 0.0 0.0 0.0 0.0 0.0 Microvascular ECTNF alpha + IL- 1beta Microvascular 0.0 0.0 0.0 0.0 0.0 0.0 Dermal ECnone Microsvasular 0.0 0.0 0.0 0.0 0.0 0.0 Dermal EC TNF alpha + IL-1beta Bronchial 0.0 0.0 0.0 0.0 0.0 0.0 epithelium TNF alpha + IL1betaSmall airway 0.5 0.5 0.5 0.0 0.0 0.0 epithelium none Small airway 4.03.8 2.1 6.2 6.3 0.0 epithelium TNF alpha + IL- 1beta Coronery artery 0.00.0 0.0 0.0 0.0 0.0 SMC rest Coronery artery 0.0 0.0 0.0 0.0 0.0 0.0 SMCTNF alpha + IL-1beta Astrocytes rest 0.0 0.0 0.0 0.0 0.0 0.0 Astrocytes0.0 0.0 0.0 0.0 0.0 0.0 TNF alpha + IL- 1beta KU-812 (Basophil) 0.0 0.00.0 0.0 0.0 0.0 rest KU-812 (Basophil) 0.0 0.0 0.0 0.0 0.0 0.0PMA/ionomycin CCD1106 0.0 0.0 0.0 0.0 0.0 0.0 (Keratinocytes) noneCCD1106 0.0 0.4 0.2 0.0 0.0 0.0 (Kerationcytes) TNF alpha + IL- 1betaLiver cirrhosis 5.4 5.4 6.9 3.0 1.4 0.0 Lupus kidney 0.4 0.4 0.9 0.0 0.00.0 NCI-H292 none 0.0 0.4 0.0 0.0 1.5 0.0 NCI-H292 IL-4 0.0 0.0 0.0 0.00.0 0.0 NCI-H292 IL-9 0.0 0.0 0.3 0.0 0.0 0.0 NCI-H292 IL-13 0.0 0.0 0.00.0 0.0 0.0 NCI-H292 IFN 0.0 0.0 0.0 0.0 0.0 0.0 gamma HPAEC none 0.00.0 0.0 0.0 0.0 0.0 HPAEC TNF alpha + 0.0 0.0 0.0 0.0 0.0 0.0 IL-1betaLung fibroblast 0.0 0.0 0.0 0.0 0.0 0.0 none Lung fibroblast 0.0 0.0 0.00.0 0.0 27.0 TNF alpha + IL- 1beta Lung fibroblast IL-4 0.0 0.0 0.0 0.00.0 0.0 Lung fibroblast IL-9 0.0 0.0 0.0 0.0 0.0 0.0 Lung fibroblast IL-0.0 0.0 0.0 0.0 0.0 0.0 13 Lung fibroblast 0.0 0.0 0.0 0.0 0.0 0.0 IFNgamma Dermal fibroblast 0.0 0.0 0.0 0.0 0.0 0.0 CCD1070 rest Dermalfibroblast 1.6 0.0 0.2 0.0 0.0 0.0 CCD1070 TNF alpha Dermal fibroblast0.0 0.0 0.0 0.0 0.0 0.0 CCD1070 IL- 1beta Dermal fibroblast 0.0 0.0 0.10.0 0.0 0.0 IFN gamma Dermal fibroblast 0.5 0.0 0.0 0.0 0.0 0.0 IL-4 IBDColitis 2 0.6 0.0 1.4 0.0 0.0 0.0 IBD Crohn's 1.4 1.5 2.0 0.0 0.0 0.0Colon 0.6 0.0 0.6 0.0 3.1 0.0 Lung 3.7 5.2 1.5 2.1 4.9 0.0 Thymus 0.50.0 0.2 0.0 0.0 0.0 Kidney 2.6 4.4 0.6 1.6 0.0 0.0

[0798] AI-comprehensive panel_v1.0 Summary: Ag1456 Highest expression ofthe sggcdraft_ba186014_(—)20000730_da1 transcript is found in normalcolon tissue adjacent to tissue affected by Crohn's or ulcerativecolitis (CTs=33). This transcript is also found in normal colon onpanels 1.2 and 2D. Since this transcript appears to be down regulated indiseased colon, therapeutic modulation of the expression or function ofthe this gene or its protein product, through the use proteintherapeutics, could regulate normal homeostasis of this tissue and bebeneficial for the treatment of inflammatory bowel diseases.

[0799] CNS_neurodegeneration_v1.0 Summary: Ag2446 Expressoin of thesggcdraft_ba186014_(—)20000730-da1 gene is low/undetectable in allsamples on this panel. (CTs>35). The amp plot indicates that there mayhave been a probe failure in this experiment. (Data not shown.)

[0800] Panel 1.2 Summary: Ag1456 Highest expression of thesggc_draft_ba186014_(—)20000730-da1 gene is detected in bone marrow(CT=28.9). Furthermore, the difference in expression between heart(CT=31.2) and fetal heart tissue(CT=36.2) is significant in this panel.Thus, the expression of this gene could be used to distinguish bonemarrow from the other samples in the panel. In addition, the expressionof this gene could be used to distinguish adult heart tissue from fetalheart tissue.

[0801] The sggc_draft_ba186014_(—)20000730-da1 gene is also expressed inmany tissues with metabolic function, including the heart, fetal andadult liver, skeletal muscle and adrenal gland. The protein encoded bythe sggc_draft_ba186014_(—)20000730_da1 gene is a lipase homolog and maybe involved in the dynamic mobilization of fat in these tissues.Therefore, administration of this gene product or an agonist designed toit could enhance lipolysis and may act as an effective therapy againstobesity and lipodystrophy. Conversely, an antagonist of this geneproduct may be useful in the treatment of conditions involving excessivedepletion of fat reserves, such as cachexia.

[0802] Panel 1.3D Summary: Ag1456/Ag2132/Ag2444Three out of fourexperiments using different probe and primer sets show expression of thesggc_draft_ba186014_(—)20000730_da1 gene in bone marrow (CTs=33-34) andthe lung (CT=32.4). The high expression in bone marrow is consistentwith its expression seen in Panel 1.2. Thus, the expression of this genecould be used to distinguish samples derived from bone marrow and lungfrom other tissues on this panel. Furthermore, expression of thesggc_draft_ba186014_(—)20000730-da1 gene could be used to distinguishbetween adult and fetal lung tissue.

[0803] Ag2059/Ag2446 Expression of the gene is low/undetectable (Ctvalues>35) in all samples in Panel 1.3D (data not shown).

[0804] Panel 2D Summary: Ag1456 Three experiments with the same probeand primer produce results that are in excellent agreement, with highestexpression of the sggc_draft_ba186014-20000730-da1 gene in normal lungtissue adjacent to a tumor (CTs=30-31). In addition, thesggc_draft_ba186014_(—)20000730-da1 gene appears to be overexpressed inthree pairs of normal lung tissue when compared to correspondingcancerous tissue. In addition, four of nine kidney cancers showoverexpression of this gene when compared to their respective normaladjacent tissue. Thus, the expression of this gene could be used todistinguish normal lung tissue from malignant lung tissue as well asmalignant kidney from normal kidney. Moreover, therapeutic modulation ofthe expression of the sggc_draft_ba186014_(—)20000730-da1 gene or itsgene product, through the use of small molecule drugs, antibodies orprotein therapeutics may be effective in the treatment of kidney canceror lung cancer.

[0805] Panel 4D Summary: Ag1456/Ag1899/Ag2059/Ag2132 Multipleexperiments with different probe and primer sets show highest expressionof the sggc_draft_ba186014_(—)20000730-da1 gene in resting monocytes(CTs=29-32). The gene appears to be downregulated in these cellsfollowing LPS treatment (CTs=32-34) and is not expressed at detectablelevels in macrophages. The protein encoded bysggc_draft_ba186014_(—)20000730 da1 gene is homologous to acidic lipasesand may play a role in lipid metabolism, differentiation, and activitiessuch as phagocytosis, of these cells. Therefore, therapeutic modulationof the expression or function of the sggc_draft_ba186014_(—)20000730-da1gene or its protein product, through the use protein therapeutics, couldregulate monocyte function and/or differentiation.

[0806] Conversely, modulation of the expression or activity of theputative protein encoded by this transcript by antibodies or smallmolecules can reduce or prevent the inflammatory symptoms associatedwith accumulation of monocytes observed in diseases such as asthma,allergies, inflammatory bowel disease, lupus erythematosus, orrheumatoid arthritis.

[0807] B. CG51493-01/20708613_EXT1: MEGF/Flamingo/Cadherin-like (NOV2)

[0808] Expression of gene CG51493-01 was assessed using the primer-probeset Ag1988, described in Table BA. Results of the RTQ-PCR runs are shownin Tables BB, BC, BD, BE, BF and BG. TABLE BA Probe Name Ag1988 PrimersSequences Start Position SEQ ID NO Forward 5′-tcactgctatgtgcacatcaa-3′2517 278 Probe TET-5′-catcacagatgccaacactcatcgg-3′-TAMRA 2538 279Reverse 5′-actgagtagtgggcactttgaa-3′ 2570 280

[0809] TABLE BB CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag1988, Rel.Exp. (%) Ag1988, Tissue Name Run 207794916 Tissue Name Run 207794916 AD1 Hippo 9.9 Control (Path) 3 5.5 Temporal Ctx AD 2 Hippo 23.8 Control(Path) 4 28.7 Temporal Ctx AD 3 Hippo 7.2 AD 1 Occipital Ctx 10.0 AD 4Hippo 6.7 AD 2 Occipital Ctx 0.0 (Missing) AD 5 Hippo 100.0 AD 3Occipital Ctx 5.8 AD 6 Hippo 32.3 AD 4 Occipital Ctx 24.5 Control 2Hippo 27.7 AD 5 Occipital Ctx 50.7 Control 4 Hippo 5.7 AD 6 OccipitalCtx 17.9 Control (Path) 3 3.5 Control 1 Occipital 2.0 Hippo Ctx AD 1Temporal Ctx 19.2 Control 2 Occipital 75.8 Ctx AD 2 Temporal Ctx 28.3Control 3 Occipital 16.7 Ctx AD 3 Temporal Ctx 7.5 Control 4 Occipital3.0 Ctx AD 4 Temporal Ctx 17.2 Control (Path) 1 90.1 Occipital Ctx AD 5Inf Temporal 92.7 Control (Path) 2 8.7 Ctx Occipital Ctx AD 5 SupTemporal 28.5 Control (Path) 3 2.2 Ctx Occipital Ctx AD 6 Inf Temporal37.6 Control (Path) 4 14.7 Ctx Occipital Ctx AD 6 Sup Temporal 44.4Control 1 Parietal 3.2 Ctx Ctx Control 1 Temporal 3.6 Control 2 Parietal34.9 Ctx Ctx Control 2 Temporal 44.8 Control 3 Parietal 15.3 Ctx CtxControl 3 Temporal 10.3 Control (Path) 1 90.1 Ctx Parietal Ctx Control 3Temporal 7.1 Control (Path) 2 15.4 Ctx Parietal Ctx Control (Path) 174.7 Control (Path) 3 3.3 Temporal Ctx Parietal Ctx Control (Path) 231.6 Control (Path) 4 44.1 Temporal Ctx Parietal Ctx

[0810] TABLE BC Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag1988, Run Ag1988, Run Ag1988, Run Ag1988, Run TissueName 147796787 148015671 Tissue Name 147796787 148015671 Liver 7.3 11.6Kidney (fetal) 0.4 0.1 adenocarcinoma Pancreas 0.2 1.1 Renal ca. 786-01.0 2.5 Pancreatic ca. 2.9 8.0 Renal ca. 16.5 21.0 CAPAN 2 A498 Adrenalgland 0.6 0.7 Renal ca. RXF 0.5 0.7 393 Thyroid 0.0 0.1 Renal ca. 18.017.8 ACHN Salivary gland 0.0 0.1 Renal ca. UO- 2.8 4.2 31 Pituitarygland 15.9 17.1 Renal ca. TK- 7.3 16.5 10 Brain (fetal) 15.2 17.2 Liver0.0 0.0 Brain (whole) 13.6 22.4 Liver (fetal) 0.0 0.4 Brain (amygdala)9.5 15.7 Liver ca. 11.6 18.9 (hepatoblast) HepG2 Brain (cerebellum) 11.017.8 Lung 1.3 0.0 Brain 15.1 29.9 Lung (fetal) 0.2 0.0 (hippocampus)Brain (substantia 0.5 1.3 Lung ca. 25.0 33.2 nigra) (small cell) LX-1Brain (thalamus) 6.6 10.0 Lung ca. 36.9 62.4 (small cell) NCI-H69Cerebral Cortex 100.0 100.0 Lung ca. 32.8 46.3 (s. cell var.) SHP-77Spinal cord 1.5 1.4 Lung ca. (large 0.0 1.4 cell) NCI-H460 glio/astroU87-MG 11.7 19.9 Lung ca. (non- 3.4 6.9 sm. cell) A549 glio/astro U-118-51.1 77.9 Lung ca. (non- 26.8 43.5 MG s. cell) NCI- H23 astrocytoma 2.15.1 Lung ca. (non- 5.9 11.7 SW1783 s. cell) HOP-62 neuro*; met SK-N-30.6 37.1 Lung ca. (non- 12.0 26.2 AS s. cl) NCI- H522 astrocytoma SF-3.9 7.9 Lung ca. 9.4 18.0 539 (squam.) SW 900 astrocytoma SNB- 58.2 82.4Lung ca. 17.6 25.2 75 (squam.) NCI- H596 glioma SNB-19 5.4 5.0 Mammary0.4 0.6 gland glioma U251 3.0 3.7 Breast ca.* 4.4 6.2 (pl. ef) MCF-7glioma SF-295 30.4 44.4 Breast ca.* 7.4 8.2 (pl. ef) MDA- MB-231 Heart(fetal) 0.8 0.5 Breast ca.* 21.9 30.1 (pl. ef) T47D Heart 0.0 0.0 Breastca. BT- 14.1 14.1 549 Skeletal muscle 0.9 2.2 Breast ca. 14.2 17.4(fetal) MDA-N Skeletal muscle 0.0 0.0 Ovary 0.8 0.8 Bone marrow 0.0 0.0Ovarian ca. 2.6 4.2 OVCAR-3 Thymus 0.1 0.2 Ovarian ca. 0.4 1.2 OVCAR-4Spleen 0.1 0.4 Ovarian ca. 7.0 8.2 OVCAR-5 Lymph node 0.4 0.7 Ovarianca. 33.7 59.9 OVCAR-8 Colorectal 1.4 1.5 Ovarian ca. 0.4 1.1 IGROV-1Stomach 0.0 1.2 Ovarian ca.* 0.4 0.7 (ascites) SK- OV-3 Small intestine0.2 0.3 Uterus 0.1 0.2 Colon ca. SW480 31.9 45.7 Placenta 0.7 1.1 Colonca.* 11.0 18.7 Prostate 0.0 0.0 SW620(SW480 met) Colon ca. HT29 5.2 10.6Prostate ca.* 2.0 5.1 (bone met) PC-3 Colon ca. HCT- 0.8 2.8 Testis 4.55.6 116 Colon ca. CaCo-2 40.1 51.4 Melanoma 1.5 3.9 Hs668(A).T Colon ca.7.7 10.2 Melanoma* 3.3 5.5 tissue(ODO3866) (met) Hs688(B).T Colon ca.HCC- 32.3 27.5 Melanoma 0.1 5.0 2998 UACC-62 Gastric ca.* (liver 5.9 8.0Melanoma 2.5 4.8 met) NCI-N87 M14 Bladder 0.3 0.6 Melanoma 3.6 11.3 LOXIMVI Trachea 0.0 0.4 Melanoma* 3.8 5.8 (met)SK- MEL-5 Kidney 0.0 0.1Adipose 0.2 0.3

[0811] TABLE BD Panel 2D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel.Exp. (%) Ag1988, Run Ag1988, Run Ag1988, Run Ag1988, Run Tissue Name148015699 151268165 Tissue Name 148015699 151268165 Normal Colon 5.1 7.6Kidney 0.4 0.5 Margin 8120608 CC Well to Mod 12.7 12.5 Kidney Cancer 1.41.1 Diff (ODO3866) 8120613 CC Margin 0.7 2.0 Kidney 1.6 1.2 (ODO3866)Margin 8120614 CC Gr.2 7.1 8.1 Kidney Cancer 2.5 1.1 rectosigmoid9010320 (ODO3868) CC Margin 0.6 0.4 Kidney 1.1 1.8 (ODO3868) Margin9010321 CC Mod Diff 11.0 7.9 Normal Uterus 1.7 0.0 (ODO3920) CC Margin6.0 2.8 Uterus Cancer 3.2 3.3 (ODO3920) 064011 CC Gr.2 ascend 40.1 25.7Normal 0.2 0.5 colon Thyroid (ODO3921) CC Margin 0.8 0.5 Thyroid 2.3 2.1(ODO3921) Cancer 064010 CC from Partial 1.4 1.3 Thyroid 2.0 1.1Hepatectomy Cancer (ODO4309) A302152 Mets Liver Margin 0.2 0.5 Thyroid2.5 1.0 (ODO4309) Margin A302153 Colon mets to 14.5 11.8 Normal Breast4.1 3.5 lung (OD04451- 01) Lung Margin 2.1 3.4 Breast Cancer 5.7 3.2(OD04451-02) (OD04566) Normal Prostate 0.9 0.6 Breast Cancer 100.0 100.06546-1 (OD04590-01) Prostate Cancer 2.6 2.4 Breast Cancer 63.7 56.3(OD04410) Mets (OD04590-03) Prostate Margin 1.7 2.0 Breast Cancer 50.747.0 (OD04410) Metastasis (OD04655-05) Prostate Cancer 1.6 2.2 BreastCancer 3.6 3.4 (OD04720-01) 064006 Prostate Margin 1.2 2.7 Breast Cancer4.0 7.1 (OD04720-02) 1024 Normal Lung 1.3 1.4 Breast Cancer 26.2 27.2061010 9100266 Lung Met to 5.7 4.7 Breast Margin 10.4 7.4 Muscle 9100265(ODO4286) Muscle Margin 0.2 1.0 Breast Cancer 6.4 6.6 (ODO4286) A209073Lung Malignant 28.1 19.2 Breast Margin 2.4 3.4 Cancer A2090734 (OD03126)Lung Margin 2.1 1.1 Normal Liver 0.4 0.3 (OD03126) Lung Cancer 2.9 1.4Liver Cancer 9.3 8.0 (OD04404) 064003 Lung Margin 0.8 0.7 Liver Cancer1.1 0.4 (OD04404) 1025 Lung Cancer 1.6 1.5 Liver Cancer 1.6 1.0(OD04565) 1026 Lung Margin 2.3 1.1 Liver Cancer 0.9 0.5 (OD04565) 6004-TLung Cancer 12.9 10.8 Liver Tissue 2.7 3.2 (OD04237-01) 6004-N LungMargin 1.7 0.9 Liver Cancer 0.5 1.5 (OD04237-02) 6005-T Ocular Mel Met0.7 0.6 Liver Tissue 0.0 0.3 to Liver 6005-N (ODO4310) Liver Margin 0.01.0 Normal 3.2 3.7 (ODO4310) Bladder Melanoma Mets 25.0 16.2 Bladder 6.23.9 to Lung Cancer 1023 (OD04321) Lung Margin 1.3 0.2 Bladder 9.3 6.1(OD04321) Cancer A302173 Normal Kidney 2.3 0.9 Bladder 58.6 41.2 Cancer(OD04718-01) Kidney Ca, 9.7 5.6 Bladder 2.6 0.4 Nuclear grade 2 Normal(OD04338) Adjacent (OD04718-03) Kidney Margin 0.8 1.4 Normal Ovary 1.20.5 (OD04338) Kidney Ca 1.3 1.4 Ovarian 1.7 3.6 Nuclear grade Cancer 1/2(OD04339) 064008 Kidney Margin 2.0 0.5 Ovarian 14.1 8.4 (OD04339) Cancer(OD04768-07) Kidney Ca, Clear 1.5 0.9 Ovary Margin 1.3 0.6 cell type(OD04768-08) (OD04340) Kidney Margin 0.8 2.5 Normal 2.6 3.5 (OD04340)Stomach Kidney Ca, 1.0 0.4 Gastric Cancer 2.4 2.2 Nuclear grade 39060358 (OD04348) Kidney Margin 1.1 1.4 Stomach 1.9 0.8 (OD04348) Margin9060359 Kidney Cancer 0.5 0.5 Gastric Cancer 18.3 17.7 (OD04622-01)9060395 Kidney Margin 0.0 0.2 Stomach 6.9 3.7 (OD04622-03) Margin9060394 Kidney Cancer 6.0 4.5 Gastric Cancer 11.0 12.7 (OD04450-01)9060397 Kidney Margin 1.0 0.8 Stomach 0.5 0.6 (OD04450-03) Margin9060396 Kidney Cancer 2.2 3.8 Gastric Cancer 22.2 15.5 8120607 064005

[0812] TABLE BE Panel 3D Rel. Exp. (%) Rel. Exp. (%) Ag1988, Run Ag1988,Run Tissue Name 170745547 Tissue Name 170745547 Daoy-Medulloblastoma 0.6Ca Ski-Cervical epidermoid 7.0 carcinoma (metastasis)TE671-Medulloblastoma 0.7 ES-2-Ovarian clear cell 0.5 carcinoma D283Med- 3.3 Ramos-Stimulated with 0.9 Medulloblastoma PMA/ionomycin 6 hPFSK-1-Primitive 0.7 Ramos-Stimulated with 0.3 NeuroectodermalPMA/ionomycin 14 h XF-498-CNS 1.8 MEG-01-Chronic 0.3 myelogenousleukemia (megokaryoblast) SNB-78-Glioma 1.1 Raji-Burkitt's lymphoma 0.5SF-268-Glioblastoma 1.6 Daudi-Burkitt's lymphoma 0.4 T98G-Glioblastoma5.8 U266-B-cell plasmacytoma 1.6 SK-N-SH- 4.8 CA46-Burkitt's lymphoma0.0 Neuroblastoma (metastasis) SF-295-Glioblastoma 3.0 RL-non-Hodgkin'sB-cell 0.0 lymphoma Cerebellum 8.1 JM1-pre-B-cell lymphoma 0.0Cerebellum 5.4 Jurkat-T cell leukemia 0.2 NCI-H292- 4.0TF-1-Erythroleukemia 1.3 Mucoepidermoid lung carcinoma DMS-114-Smallcell 6.4 HUT 78-T-cell lymphoma 2.8 lung cancer DMS-79-Small cell lung100.0 U937-Histiocytic lymphoma 0.2 cancer NCI-H146-Small cell 13.2KU-812-Myelogenous 0.1 lung cancer leukemia NCI-H526-Small cell 17.0769-P-Clear cell renal 0.1 lung cancer carcinoma NCI-N417-Small cell 4.3Caki-2-Clear cell renal 0.3 lung cancer carcinoma NCI-H82-Small cell 2.3SW 839-Clear cell renal 0.0 lung cancer carcinoma NCI-H157-Squamous 1.4G401-Wilms' tumor 0.5 cell lung cancer (metastasis) NCI-H1155-Large cell17.3 Hs766T-Pancreatic 3.0 lung cancer carcinoma (LN metastasis)NCI-H1299-Large cell 3.7 CAPAN-1-Pancreatic 1.7 lung canceradenocarcinoma (liver metastasis) NCI-H727-Lung 3.9 SU86.86-Pancreatic0.4 carcinoid carcinoma (liver metastasis) NCI-UMC-11-Lung 7.8BxPC-3-Pancreatic 2.2 carcinoid adenocarcinoma LX-1-Small cell lung 5.6HPAC-Pancreatic 3.5 cancer adenocarcinoma Colo-205-Colon cancer 0.6 MIAPaCa-2-Pancreatic 0.4 carcinoma KM12-Colon cancer 0.9 CFPAC-1-Pancreaticductal 0.4 adenocarcinoma KM20L2-Colon cancer 1.2 PANC-1-Pancreatic 1.6epithelioid ductal carcinoma NCI-H716-Colon cancer 21.8 T24-Bladdercarcinma 2.0 (transitional cell) SW-48-Colon 0.9 5637-Bladder carcinoma1.8 adenocarcinoma SW1116-Colon 0.3 HT-1197-Bladder carcinoma 0.0adenocarcinoma LS 174T-Colon 0.8 UM-UC-3-Bladder carcinma 0.3adenocarcinoma (transitional cell) SW-948-Colon 0.0A204-Rhabdomyosarcoma 4.8 adenocarcinoma SW-480-Colon 1.6HT-1080-Fibrosarcoma 1.6 adenocarcinoma NCI-SNU-5-Gastric 2.2MG-63-Osteosarcoma 0.1 carcinoma KATO III-Gastric 5.3SK-LMS-1-Leiomyosarcoma 8.5 carcinoma (vulva) NCI-SNU-16-Gastric 0.2SJRH30-Rhabdomyosarcoma 0.5 carcinoma (met to bone marrow)NCI-SNU-1-Gastric 4.2 A431-Epidermoid carcinoma 0.0 carcinomaRF-1-Gastric 0.0 WM266-4-Melanoma 3.3 adenocarcinoma RF-48-Gastric 0.3DU 145-Prostate carcinoma 0.0 adenocarcinoma (brain metastasis)MKN-45-Gastric 5.8 MDA-MB-468-Breast 0.0 carcinoma adenocarcinomaNCI-N87-Gastric 0.2 SCC-4-Squamous cell 0.0 carcinoma carcinoma oftongue OVCAR-5-Ovarian 0.0 SCC-9-Squamous cell 0.0 carcinoma carcinomaof tongue RL95-2-Uterine 0.5 SCC-15-Squamous cell 0.0 carcinomacarcinoma of tongue HelaS3-Cervical 1.5 CAL 27-Squamous cell 0.1adenocarcinoma carcinoma of tongue

[0813] TABLE BF Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag1988, Run Ag1988,Run Tissue Name 152701692 Tissue Name 152701692 Secondary Th1 act 2.1HUVEC IL-1beta 0.0 Secondary Th2 act 3.6 HUVEC IFN gamma 0.0 SecondaryTr1 act 3.3 HUVEC TNF alpha + IFN 0.3 gamma Secondary Th1 rest 1.0 HUVECTNF alpha + IL4 1.2 Secondary Th2 rest 0.2 HUVEC IL-11 0.0 Secondary Tr1rest 0.4 Lung Microvascular EC 1.9 none Primary Th1 act 5.8 LungMicrovascular EC 1.5 TNF alpha + IL-1beta Primary Th2 act 10.4Microvascular Dermal EC 0.8 none Primary Tr1 act 4.5 MicrosvasularDermal EC 1.6 TNF alpha + IL-1beta Primary Th1 rest 3.3 Bronchialepithelium 0.4 TNF alpha + IL1beta Primary Th2 rest 1.1 Small airwayepithelium 0.0 none Primary Tr1 rest 2.1 Small airway epithelium 7.4 TNFalpha + IL-1beta CD45RA CD4 2.2 Coronery artery SMC rest 3.4 lymphocyteact CD45RO CD4 2.3 Coronery artery SMC 1.4 lymphocyte act TNF alpha +IL-1beta CD8 lymphocyte act 3.7 Astrocytes rest 7.6 Secondary CD8 1.7Astrocytes TNF alpha + 2.3 lymphocyte rest IL-1beta Secondary CD8 3.7KU-812 (Basophil) rest 1.7 lymphocyte act CD4 lymphocyte none 1.4 KU-812(Basophil) 6.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 2.0 CCD1106(Keratinocytes) 9.5 CD95 CH11 none LAK cells rest 0.8 CCD1106(Keratinocytes) 2.4 TNF alpha + IL-1beta LAK cells IL-2 3.9 Livercirrhosis 1.1 LAK cells IL-2 + IL-12 2.2 Lupus kidney 0.0 LAK cellsIL-2 + IFN 5.9 NCI-H292 none 65.5 gamma LAK cells IL-2 + IL-18 5.4NCI-H292 IL-4 92.7 LAK cells 2.6 NCI-H292 IL-9 100.0 PMA/ionomycin NKCells IL-2 rest 2.7 NCI-H292 IL-13 53.2 Two Way MLR 3 day 1.8 NCI-H292IFN gamma 48.0 Two Way MLR 5 day 1.6 HPAEC none 0.0 Two Way MLR 7 day3.4 HPAEC TNF alpha + IL-1 1.1 beta PBMC rest 1.5 Lung fibroblast none3.7 PBMC PWM 4.4 Lung fibroblast TNF 2.7 alpha + IL-1beta PBMC PHA-L 2.3Lung fibroblast IL-4 7.6 Ramos (B cell) none 18.3 Lung fibroblast IL-93.7 Ramos (B cell) 88.3 Lung fibroblast IL-13 3.2 ionomycin Blymphocytes PWM 14.1 Lung fibroblast IFN 3.9 gamma B lymphocytes CD40L3.6 Dermal fibroblast 3.1 and IL-4 CCD1070 rest EOL-1 dbcAMP 16.7 Dermalfibroblast 8.0 CCD1070 TNF alpha EOL-1 dbcAMP 13.0 Dermal fibroblast 5.9PMA/ionomycin CCD1070 IL-1beta Dendritic cells none 1.0 Dermalfibroblast IFN 1.2 gamma Dendritic cells LPS 0.3 Dermal fibroblast IL-41.9 Dendritic cells anti- 1.0 IBD Colitis 2 0.1 CD40 Monocytes rest 1.1IBD Crohn's 0.0 Monocytes LPS 1.1 Colon 6.4 Macrophages rest 0.8 Lung3.7 Macrophages LPS 0.0 Thymus 1.2 HUVEC none 0.2 Kidney 1.9 HUVECstarved 0.4

[0814] TABLE BG Panel CNS_1 Rel. Exp. (%) Ag1988, Rel. Exp. (%) Ag1988,Tissue Name Run 171628544 Tissue Name Run 171628544 BA4 Control 18.7BA17 PSP 25.5 BA4 Control2 40.3 BA17 PSP2 16.6 BA4 11.9 Sub NigraControl 11.3 Alzheimer's2 BA4 Parkinson's 34.4 Sub Nigra Control2 17.1BA4 84.1 Sub Nigra 6.1 Parkinson's2 Alzheimer's2 BA4 26.1 Sub Nigra 23.3Huntington's Parkinson's2 BA4 12.7 Sub Nigra 34.2 Huntington's2Huntington's BA4 PSP 4.7 Sub Nigra 17.1 Huntington's2 BA4 PSP2 15.9 SubNigra PSP2 5.1 BA4 Depression 23.2 Sub Nigra 2.1 Depression BA4 4.7 SubNigra 7.7 Depression2 Depression2 BA7 Control 61.6 Glob Palladus 6.8Control BA7 Control2 26.2 Glob Palladus 6.1 Control2 BA7 13.3 GlobPalladus 8.8 Alzheimer's2 Alzheimer's BA7 Parkinson's 18.8 Glob Palladus3.8 Alzheimer's2 BA7 62.9 Glob Palladus 57.4 Parkinson's2 Parkinson'sBA7 66.9 Glob Palladus 8.2 Huntington's Parkinson's2 BA7 54.7 GlobPalladus PSP 1.7 Huntington's2 BA7 PSP 43.8 Glob Palladus PSP2 3.9 BA7PSP2 30.4 Glob Palladus 3.8 Depression BA7 Depression 13.6 Temp PoleControl 10.5 BA9 Control 19.3 Temp Pole Control2 45.1 BA9 Control2 100.0Temp Pole 9.6 Alzheimer's BA9 Alzheimer's 9.5 Temp Pole 2.6 Alzheimer's2BA9 17.1 Temp Pole 36.9 Alzheimer's2 Parkinson's BA9 Parkinson's 27.2Temp Pole 32.5 Parkinson's2 BA9 62.0 Temp Pole 37.6 Parkinson's2Huntington's BA9 37.9 Temp Pole PSP 2.9 Huntington's BA9 19.3 Temp PolePSP2 13.1 Huntington's2 BA9 PSP 11.0 Temp Pole 11.7 Depression2 BA9 PSP29.3 Cing Gyr Control 53.2 BA9 Depression 9.4 Cing Gyr Control2 40.1 BA915.0 Cing Gyr 12.1 Depression2 Alzheimer's BA17 Control 43.8 Cing Gyr8.5 Alzheimer's2 BA17 Control2 70.7 Cing Gyr Parkinson's 27.5 BA17 15.7Cing Gyr 35.4 Alzheimer's2 Parkinson's2 BA17 40.6 Cing Gyr 37.6Parkinson's Huntington's BA17 72.2 Cing Gyr 25.5 Parkinson's2Huntington's2 BA17 42.0 Cing Gyr PSP 14.3 Huntington's BA17 24.8 CingGyr PSP2 4.8 Huntington's2 BA17 9.4 Cing Gyr Depression 14.0 DepressionBA17 33.4 Cing Gyr 12.1 Depression2 Depression2

[0815] CNS_neurodegeneration_v1.0 Summary: Ag1988 The CG51493-01 gene isexpressed most highly in the cerebral cortex, and exhibits brainpreferential expression. No specific association is notable between geneexpression level and Alzheimer's disease in CNS_neurodegeneration_v10.0panel. Please see Panel 1.3D for discussion of potential utility of thisgene in the central nervous system.

[0816] Panel 1.3D Summary: Ag1988 Two experiments with the same probeand primer produce results that are in excellent agreement, with highestexpression of the CG51493-01 gene in the cerebral cortex (CTs=27-29).This peak expression of the gene in the cerebral cortex, combined with adendritic field-defining function for flamingo, suggests that theflamingo homolog encoded by this gene may control dendritic fieldformation in the brain. Dendritic degeneration is a prominent feature ofAlzheimer's disease. Since flamingo acts as an inhibitory molecule inthe expansion of dendritic fields, targeting this gene product withinhibitory small molecules or antibodies may foster neurite outgrowth byinterfering with this endogenous neurite outgrowth inhibitor. Thus, thismay be useful in treating the pathological neurite degeneration ofAlzheimer's disease or other neurodegenerative diseases.

[0817] Among tissues with metabolic function, this gene is moderatelyexpressed in the pituitary (CTs=30) and fetal skeletal muscle (CTs=34).Furthermore, this gene is expressed at much higher levels in fetalskeletal muscle than in adult skeletal muscle (CTs0) and thus couldpotentially be used to differentiate between the two sources of thetissue.

[0818] This putative protein has a domain found in the extracellularpart of some hormone receptors including the calcitonin receptor,corticotropin releasing factor receptor 1, diuretic hormone receptor,glucagon-like peptide 1 receptor, and parathyroid hormone peptidereceptor. Thus, as a potential G-protein coupled receptor, this geneproduct may be a small molecule drug target for the treatment ofdiseases that involve the pituitary gland, including endocrinedysfunctions, diabetes, obesity, and growth and reproductive disorders.

[0819] Overall, there is a predominant expression pattern associatedwith cancer cell lines, when compared to normal adult tissues. Evidencefor this are the clusters of expression of this gene in lung, renal,prostate and melanoma cell lines. This data suggest that the expressionof this gene might be associated with these forms of cancer and thus,therapeutic modulation of this gene might be of use in the treatment ofthese cancers

[0820] Panel 2D Summary: Ag1988 The expression of the CG51493-01 ishighest in breast cancer (CTs=28-29) in two experiments with the sameprobe and primer set. colon, breast and bladder cancers express thisgene at a higher level than the normal adjacent tissue. These dataindicate that the expression of this gene might be associated with theseforms of cancer and could be used as a diagnostic marker. Furthermore,therapeutic modulation of this gene might be of use in the treatment ofthese cancers.

[0821] Panel 3D Summary: Ag1988 The CG51493-01 gene is widely expressedin the cancer cell lines on this panel including colon, lung, gastric,brain, uterine, pancreatic and some sarcoma cell lines. This suggeststhat expression of this gene is potentially useful for cell growth andproliferation and that expression of this gene might be associated withthese cancer tissues Thus, expression of this gene could potentially beused as a diagnostic marker and therapeutic modulation of this genemight be of use in the treatment of cancer.

[0822] Panel 4D Summary: Ag1988 The expression of the CG51493-01transcript is moderate in the pulmonary muco-epidermoid cell lineNCI-H292 and is up-regulated by IL-4 and IL-9 treatment (CTs=29.5). Bothcytokines have been reported to induce mucin gene expression in thiscell line and therefore have been postulated to contribute to thepathogenesis of chronic obstructive pulmonary disease, emphysema andasthma. This transcript encodes for a protocadherin flamingo 1 likemolecule, which belongs to the cadherin family. Members of the cadherinfamily play an important role in specific cell-cell adhesion events.Thus, modulation of the expression levels or functionality of thisputative protein through the application of antibodies or smallmolecules may reduce or eliminate symptoms caused by inflammation inlung epithelia in chronic obstructive pulmonary disease, asthma,allergy, and emphysema.

[0823] This transcript is also moderately expressed in activated Ramos Bcells and at a lower but still significant level in normal activated Bcells. This suggests that therapeutics designed against this putativeprotein may reduce or prevent the accumulation of B cells in inflammedtissues and therefore be useful for the treatment of rheumatoidarthritis and lupus.

[0824] Panel CNS_(—)1 Summary: Ag1988 This panel confirms expression ofthis gene in the brain. See Panel 1.3D for discussion of utility of thisgene in the central nervous system.

[0825] C. CG55806-01: Human Factor IX (NOV3)

[0826] Expression of gene CG55806-01 was assessed using the primer-probeset Ag2613, described in Table CA. Results of the RTQ-PCR runs are shownin Tables CB, CC and CD. TABLE CA Probe Name Ag2613 Primers SequencesStart Position SEQ ID NO Forward 5′-agccacatgtcttcgatctaca-3′ 937 281Probe TET-5′-acaacatgttctgtgctggcttccat-3′-TAMRA 975 282 Reverse5′-cccactatctccttgacatgaa-3′ 1015 283

[0827] TABLE CB Panel 1.3D Rel. Exp. (%) Ag2613, Rel. Exp. (%) Ag2613,Tissue Name Run 165672326 Tissue Name Run 165672326 Liver adenocarcinoma0.0 Kidney (fetal) 10.7 Pancreas 0.0 Renal ca. 786-0 0.0 Pancreatic ca.CAPAN 2 0.0 Renal ca. A498 0.0 Adrenal gland 0.0 Renal ca. RXF 393 0.0Thyroid 0.0 Renal ca. ACHN 0.0 Salivary gland 0.0 Renal ca. UO-31 0.0Pituitary gland 0.0 Renal ca. TK-10 0.0 Brain (fetal) 0.0 Liver 100.0Brain (whole) 0.0 Liver (fetal) 76.3 Brain (amygdala) 0.0 Liver ca. 0.0(hepatoblast) HepG2 Brain (cerebellum) 0.0 Lung 0.0 Brain (hippocampus)0.0 Lung (fetal) 0.0 Brain (substantia nigra) 0.0 Lung ca. (small cell)0.0 LX-1 Brain (thalamus) 0.0 Lung ca. (small cell) 0.0 NCI-H69 CerebralCortex 0.0 Lung ca. (s.cell var.) 0.3 SHP-77 Spinal cord 0.0 Lung ca.(large 0.0 cell)NCI-H460 glio/astro U87-MG 0.0 Lung ca. (non-sm. 0.0cell) A549 glio/astro U-118-MG 0.0 Lung ca. (non-s.cell) 0.0 NCI-H23astrocytoma SW1783 0.0 Lung ca. (non-s.cell) 0.0 HOP-62 neuro*; metSK-N-AS 0.0 Lung ca. (non-s.cl) 0.0 NCI-H522 astrocytoma SF-539 0.0 Lungca. (squam.) 0.0 SW 900 astrocytoma SNB-75 0.0 Lung ca. (squam.) 0.0NCI-H596 glioma SNB-19 0.0 Mammary gland 0.0 glioma U251 0.0 Breast ca.*(pl.ef) 0.0 MCF-7 glioma SF-295 0.0 Breast ca.* (pl.ef) 0.2 MDA-MB-231Heart (fetal) 0.0 Breast ca.* (pl.ef) 0.0 T47D Heart 0.0 Breast ca.BT-549 0.0 Skeletal muscle (fetal) 0.0 Breast ca. MDA-N 0.0 Skeletalmuscle 0.0 Ovary 0.0 Bone marrow 0.0 Ovarian ca. OVCAR-3 0.0 Thymus 0.0Ovarian ca. OVCAR-4 0.0 Spleen 0.0 Ovarian ca. OVCAR-5 0.0 Lymph node0.0 Ovarian ca. OVCAR-8 0.0 Colorectal 0.0 Ovarian ca. IGROV-1 0.0Stomach 0.0 Ovarian ca.* (ascites) 0.0 SK-OV-3 Small intestine 0.0Uterus 0.0 Colon ca. SW480 0.0 Placenta 0.0 Colon ca.* 0.0 Prostate 0.0SW620(SW480 met) Colon ca. HT29 0.0 Prostate ca.* (bone 0.0 met)PC-3Colon ca. HCT-116 0.0 Testis 0.0 Colon ca. CaCo-2 0.0 Melanoma 0.0Hs688(A).T Colon ca. 0.0 Melanoma* (met) 0.0 tissue(ODO3866) Hs688(B).TColon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca.* (liver met) 0.0Melanoma M14 0.0 NCI-N87 Bladder 0.0 Melanoma LOX 0.0 IMVI Trachea 0.0Melanoma* (met) 0.0 SK-MEL-5 Kidney 0.0 Adipose 0.0

[0828] TABLE CC Panel 2.2 Rel. Exp. (%) Rel. Exp. (%) Ag2613, RunAg2613, Run Tissue Name 175128272 Tissue Name 175128272 Normal Colon 0.4Kidney Margin 0.0 (OD04348) Colon cancer 0.0 Kidney malignant cancer 0.0(OD06064) (OD06204B) Colon Margin 0.0 Kidney normal adjacent tissue 0.0(OD06064) (OD06204E) Colon cancer 0.0 Kidney Cancer 0.0 (OD06159)(OD04450-01) Colon Margin 0.0 Kidney Margin 0.0 (OD06159) (OD04450-03)Colon cancer 0.0 Kidney Cancer 8120613 0.0 (OD06297-04) Colon Margin 0.0Kidney Margin 0.0 (OD06297-015) 8120614 CC Gr.2 ascend colon 0.0 KidneyCancer 9010320 0.0 (ODO3921) CC Margin (ODO3921) 0.0 Kidney Margin 0.09010321 Colon cancer metastasis 0.0 Kidney Cancer 8120607 0.0 (OD06104)Lung Margin 0.0 Kidney Margin 0.0 (OD06104) 8120608 Colon mets to lung0.1 Normal Uterus 0.1 (OD04451-01) Lung Margin 0.0 Uterine Cancer 0640110.0 (OD04451-02) Normal Prostate 0.0 Normal Thyroid 0.0 Prostate Cancer0.0 Thyroid Cancer 064010 0.0 (OD04410) Prostate Margin 0.0 ThyroidCancer 0.0 (OD04410) A302152 Normal Ovary 0.0 Thyroid Margin 0.0 A302153Ovarian cancer 0.0 Normal Breast 0.0 (OD06283-03) Ovarian Margin 0.0Breast Cancer 1.5 (OD06283-07) (OD04566) Ovarian Cancer 064008 2.1Breast Cancer 1024 0.0 Ovarian cancer 1.0 Breast Cancer 0.2 (OD06145)(OD04590-01) Ovarian Margin 0.2 Breast Cancer Mets 0.0 (OD06145)(OD04590-03) Ovarian cancer 0.0 Breast Cancer 0.0 (OD06455-03)Metastasis (OD04655- 05) Ovarian Margin 0.0 Breast Cancer 064006 0.1(OD06455-07) Normal Lung 0.2 Breast Cancer 9100266 0.0 Invasive poordiff. lung 0.0 Breast Margin 9100265 0.0 adeno (ODO4945-01 Lung Margin0.0 Breast Cancer A209073 0.0 (ODO4945-03) Lung Malignant Cancer 0.0Breast Margin 0.0 (OD03126) A2090734 Lung Margin 0.0 Breast cancer 0.0(OD03126) (OD06083) Lung Cancer 0.0 Breast cancer node 0.0 (OD05014A)metastasis (OD06083) Lung Margin 0.4 Normal Liver 100.0 (OD05014B) Lungcancer (OD06081) 0.0 Liver Cancer 1026 1.9 Lung Margin 0.0 Liver Cancer1025 60.3 (OD06081) Lung Cancer 0.0 Liver Cancer 6004-T 42.6(OD04237-01) Lung Margin 0.0 Liver Tissue 6004-N 1.4 (OD04237-02) OcularMelanoma 0.0 Liver Cancer 6005-T 3.3 Metastasis Ocular Melanoma 51.4Liver Tissue 6005-N 33.7 Margin (Liver) Melanoma Metastasis 0.0 LiverCancer 064003 59.0 Melanoma Margin 0.0 Normal Bladder 0.0 (Lung) NormalKidney 0.0 Bladder Cancer 1023 0.0 Kidney Ca, Nuclear 0.0 Bladder Cancer0.0 grade 2 (OD04338) A302173 Kidney Margin 0.0 Normal Stomach 0.1(OD04338) Kidney Ca Nuclear 0.0 Gastric Cancer 9060397 0.0 grade 1/2(OD04339) Kidney Margin 0.0 Stomach Margin 0.0 (OD04339) 9060396 KidneyCa, Clear cell 0.0 Gastric Cancer 9060395 0.2 type (OD04340) KidneyMargin 0.0 Stomach Margin 0.0 (OD04340) 9060394 Kidney Ca, Nuclear 0.0Gastric Cancer 064005 0.0 grade 3 (OD04348)

[0829] TABLE CD Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2613, Run Ag2613,Run Tissue Name 164399517 Tissue Name 164399517 Secondary Th1 act 0.0HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 SecondaryTr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVECTNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 LungMicrovascular EC 0.0 TNF alpha + IL-1beta Primary Th2 act 0.0Microvascular Dermal EC 0.0 none Primary Tr1 act 0.0 MicrosvasularDermal EC 0.0 TNF alpha + IL-1beta Primary Th1 rest 0.0 Bronchialepithelium 0.0 TNF alpha + IL1beta Primary Th2 rest 0.0 Small airwayepithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 0.0 TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0 lymphocyteact CD45RO CD4 0.0 Coronery artery SMC 0.0 lymphocyte act TNF alpha +IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 Secondary CD8 0.0Astrocytes TNF alpha + 0.0 lymphocyte rest IL-1beta Secondary CD8 0.0KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 0.0 KU-812(Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106(Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 0.0 CCD1106(Keratinocytes) 0.0 TNF alpha + IL-1beta LAK cells IL-2 0.0 Livercirrhosis 100.0 LAK cells IL-2 + IL-12 0.0 Lupus kidney 0.0 LAK cellsIL-2 + IFN 0.0 NCI-H292 none 0.0 gamma LAK cells IL-2 + IL-18 0.0NCI-H292 IL-4 0.0 LAK cells 0.0 NCI-H292 IL-9 0.0 PMA/ionomycin NK CellsIL-2 rest 0.0 NCI-H292 IL-13 0.0 Two Way MLR 3 day 0.0 NCI-H292 IFNgamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 0.0PBMC PWM 0.0 Lung fibroblast TNF 0.0 alpha + IL-1beta PBMC PHA-L 0.0Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-90.0 Ramos (B cell) 0.0 Lung fibroblast IL-13 0.0 ionomycin B lymphocytesPWM 0.0 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 0.0 Dermalfibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0PMA/ionomycin CCD1070 IL-1beta 0.0 Dendritic cells none 0.0 Dermalfibroblast IFN 0.0 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-40.0 Dendritic cells anti- 0.0 IBD Colitis 2 0.0 CD40 Monocytes rest 0.0IBD Crohn's 0.0 Monocytes LPS 0.0 Colon 0.0 Macrophages rest 0.0 Lung1.0 Macrophages LPS 0.0 Thymus 0.0 HUVEC none 0.0 Kidney 0.0 HUVECstarved 0.0

[0830] Panel 1.3D Summary: Ag2613 Expression of the CG55806-01 gene islimited to the liver and fetal kidney samples on this panel(CTs=27-31).This gene encodes a protein that is homologous to factor IX. Thesecreted form of the protein may be present in the circulatory sysytemand exhibit effects that are unrelated to the site of synthesis. Basedon the expression profile of this gene, expression of this gene could beused to differentiate between liver derived tissue and other tissues.Furthermore, therapeutic modulation of the expression or function ofthis gene product may be effective in correcting the alterations tocoagulation system seen in hemophilia and other liver related disease.

[0831] Panel 2.2 Summary: Ag2613 Expression of the CG55806-01 gene ishighest in samples derived from liver (CT=27.9), a result that isconsistent with the results seen in Panel 1.3D. Therefore, expression ofthis gene could be used to differentiate between normal sections ofliver as compared to tumors that are secondary metastases from othersites (such as melanoma).

[0832] Panel 4D Summary: Ag2613 The CG55806-01 transcript is highlyexpressed in cirrhotic liver tissue (CT=27.8). This liver specificexpression is also seen in the previous panels, suggesting that thistranscript or the protein it encodes could be used as a diagnosticmarker for liver tissue.

[0833] D. CG55936-01: Carbonic Anhydrase IV precursor (NOV4)

[0834] Expression of gene CG55936-01 was assessed using the primer-probeset Ag1677, described in Table DA. Results of the RTQ-PCR runs are shownin Tables DB, DC, DD, DE and DF. TABLE DA Probe Name Ag1677 PrimersSequences Start Position SEQ ID NO Forward 5′-cccattcagcttcacagaga-3′260 284 Probe TET-5′-cagatcctggcattctctcagaagctg-3′-TAMRA 232 285Reverse 5′-atgctcactgtctgttccttgt-3′ 203 286

[0835] TABLE DB CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag1677, Rel.Exp. (%) Ag1677, Tissue Name Run 209733901 Tissue Name Run 209733901 AD1 Hippo 9.9 Control (Path) 3 8.2 Temporal Ctx AD 2 Hippo 16.7 Control(Path) 4 75.8 Temporal Ctx AD 3 Hippo 5.3 AD 1 Occipital Ctx 14.4 AD 4Hippo 26.2 AD 2 Occipital Ctx 2.5 (Missing) AD 5 Hippo 40.6 AD 3Occipital Ctx 5.9 AD 6 Hippo 15.6 AD 4 Occipital Ctx 48.6 Control 2Hippo 19.9 AD 5 Occipital Ctx 20.3 Control 4 Hippo 21.8 AD 6 OccipitalCtx 19.3 Control (Path) 3 8.5 Control 1 Occipital 11.4 Hippo Ctx AD 1Temporal Ctx 8.7 Control 2 Occipital 25.7 Ctx AD 2 Temporal Ctx 75.3Control 3 Occipital 18.0 Ctx AD 3 Temporal Ctx 5.1 Control 4 Occipital9.3 Ctx AD 4 Temporal Ctx 92.0 Control (Path) 1 46.0 Occipital Ctx AD 5Inf Temporal 100.0 Control (Path) 2 48.0 Ctx Occipital Ctx AD 5 SupTemporal 37.9 Control (Path) 3 4.2 Ctx Occipital Ctx AD 6 Inf Temporal19.5 Control (Path) 4 7.8 Ctx Occipital Ctx AD 6 Sup Temporal 15.7Control 1 Parietal 26.6 Ctx Ctx Control 1 Temporal 11.7 Control 2Parietal 16.0 Ctx Ctx Control 2 Temporal 21.6 Control 3 Parietal 30.4Ctx Ctx Control 3 Temporal 17.1 Control (Path) 1 24.0 Ctx Parietal CtxControl 3 Temporal 25.3 Control (Path) 2 47.3 Ctx Parietal Ctx Control(Path) 1 70.7 Control (Path) 3 4.5 Temporal Ctx Parietal Ctx Control(Path) 2 56.3 Control (Path) 4 15.7 Temporal Ctx Parietal Ctx

[0836] TABLE DC General_screening_panel_v1.4 Rel. Exp. (%) Ag1677, Rel.Exp. (%) Ag1677, Tissue Name Run 208021859 Tissue Name Run 208021859Adipose 21.3 Renal ca. TK-10 0.6 Melanoma* 0.3 Bladder 6.3 Hs688(A).TMelanoma* 0.1 Gastric ca. (liver met.) 0.2 HS688(B).T NCI-N87 Melanoma*M14 0.1 Gastric ca. KATO III 0.1 Melanoma* 0.2 Colon ca. SW-948 0.3LOXIMVI Melanoma* SK- 0.7 Colon ca. SW480 0.2 MEL-5 Squamous cell 0.2Colon ca.* (SW480 0.4 carcinoma SCC-4 met) SW620 Testis Pool 4.7 Colonca. HT29 1.3 Prostate ca.* (bone 0.3 Colon ca. HCT-116 0.4 met) PC-3Prostate Pool 3.0 Colon ca. CaCo-2 3.5 Placenta 6.3 Colon cancer tissue1.9 Uterus Pool 2.0 Colon ca. SW1116 0.6 Ovarian ca. 0.2 Colon ca.Colo-205 0.4 OVCAR-3 Ovarian ca. SK-OV-3 0.2 Colon ca. SW-48 0.4 Ovarianca. 0.3 Colon Pool 6.2 OVCAR-4 Ovarian ca. 0.3 Small Intestine Pool 3.8OVCAR-5 Ovarian ca. IGROV-1 0.6 Stomach Pool 3.8 Ovarian ca. 0.8 BoneMarrow Pool 1.8 OVCAR-8 Ovary 1.8 Fetal Heart 19.1 Breast ca. MCF-7 24.0Heart Pool 21.0 Breast ca. MDA- 0.4 Lymph Node Pool 4.7 MB-231 Breastca. BT 549 23.8 Fetal Skeletal Muscle 4.4 Breast ca. T47D 0.7 SkeletalMuscle Pool 14.0 Breast ca. MDA-N 0.7 Spleen Pool 2.5 Breast Pool 3.6Thymus Pool 3.3 Trachea 2.7 CNS cancer (glio/astro) 0.1 U87-MG Lung 2.9CNS cancer (glio/astro) 1.0 U-118-MG Fetal Lung 82.4 CNS cancer 0.1(neuro;met) SK-N-AS Lung ca. NCI-N417 0.1 CNS cancer (astro) SF- 0.2 539Lung ca. LX-1 0.2 CNS cancer (astro) 0.7 SNB-75 Lung ca. NCI-H146 0.2CNS cancer (glio) 1.3 SNB-19 Lung ca. SHP-77 31.6 CNS cancer (gilo) SF-0.2 295 Lung ca. A549 0.9 Brain (Amygdala) Pool 12.1 Lung ca. NCI-H5260.5 Brain (cerebellum) 100.0 Lung ca. NCI-H23 0.3 Brain (fetal) 3.0 Lungca. NCI-H460 0.2 Brain (Hippocampus) 8.4 Pool Lung ca. HOP-62 0.2Cerebral Cortex Pool 21.2 Lung ca. NCI-H522 0.0 Brain (Substantia nigra)22.7 Pool Liver 0.4 Brain (Thalamus) Pool 14.5 Fetal Liver 0.7 Brain(whole) 22.1 Liver ca. HepG2 0.3 Spinal Cord Pool 5.3 Kidney Pool 14.8Adrenal Gland 2.9 Fetal Kidney 19.6 Pituitary gland Pool 10.4 Renal ca.786-0 0.4 Salivary Gland 5.1 Renal ca. A498 0.5 Thyroid (female) 39.5Renal ca. ACHN 0.2 Pancreatic ca. CAPAN2 0.4 Renal ca. UO-31 0.2Pancreas Pool 6.1

[0837] TABLE DD Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag1677, Run Ag1677, Run Ag1677, Run Ag1677, Run TissueName 152171910 165532764 Tissue Name 152171910 165532764 Liver 0.0 0.1Kidney (fetal) 1.9 7.0 adenocarcinoma Pancreas 14.8 23.5 Renal ca. 786-00.0 0.0 Pancreatic ca. 0.0 0.1 Renal ca. 0.0 0.2 CAPAN 2 A498 Adrenalgland 2.1 3.3 Renal ca. RXF 0.0 1.0 393 Thyroid 36.1 37.1 Renal ca. 0.00.5 ACHN Salivary gland 3.2 10.0 Renal ca. UO- 0.0 0.0 31 Pituitarygland 6.4 10.4 Renal ca. TK- 0.0 0.3 10 Brain (fetal) 0.8 1.6 Liver 0.00.9 Brain (whole) 13.2 36.6 Liver (fetal) 0.0 1.9 Brain (amygdala) 4.617.9 Liver ca. 0.0 0.0 (hepatoblast) HepG2 Brain (cerebellum) 11.1 74.2Lung 100.0 100.0 Brain 23.8 30.6 Lung (fetal) 59.5 72.2 (hippocampus)Brain (substantia 4.6 18.7 Lung ca. 0.0 1.1 nigra) (small cell) LX-1Brain (thalamus) 3.5 20.2 Lung ca. 0.0 0.2 (small cell) NCI-H69 CerebralCortex 22.4 28.3 Lung ca. 0.0 0.7 (s. cell var.) SHP-77 Spinal cord 0.96.9 Lung ca. (large 0.0 0.7 cell)NCI-H460 glio/astro U87-MG 0.0 0.1 Lungca. (non- 0.0 0.9 sm. cell) A549 glio/astro U-118- 0.0 2.2 Lung ca.(non- 0.2 1.0 MG s. cell) NCI- H23 astrocytoma 0.0 0.7 Lung ca. (non-0.0 0.3 SW1783 s. cell) HOP-62 neuro*; met SK-N- 0.0 0.5 Lung ca. (non-0.0 0.8 AS s. cl) NCI- H522 astrocytoma SF- 0.1 0.7 Lung ca. 0.0 0.7 539(squam.) SW 900 astrocytoma SNB- 0.0 1.0 Lung ca. 0.0 0.6 75 (squam.)NCI- H596 glioma SNB-19 0.0 1.0 Mammary 16.7 19.5 gland glioma U251 0.01.1 Breast ca.* 3.8 5.3 (pl. ef) MCF-7 glioma SF-295 0.0 1.2 Breast ca.*0.0 0.2 (pl. ef) MDA- MB-231 Heart (fetal) 55.5 40.6 Breast ca.* 0.0 0.7(pl. ef) T47D Heart 11.9 47.0 Breast ca. BT- 0.4 2.2 549 Skeletal muscle41.2 22.7 Breast ca. 0.0 0.9 (fetal) MDA-N Skeletal muscle 2.0 22.4Ovary 3.5 3.1 Bone marrow 4.8 12.1 Ovarian ca. 0.0 1.3 OVCAR-3 Thymus0.4 1.9 Ovarian ca. 0.0 0.0 OVCAR-4 Spleen 2.3 3.2 Ovarian ca. 0.0 0.6OVCAR-5 Lymph node 4.2 15.7 Ovarian ca. 0.0 1.4 OVCAR-8 Colorectal 57.464.2 Ovarian ca. 0.0 0.3 IGROV-1 Stomach 11.6 20.9 Ovarian ca.* 0.0 0.7(ascites) SK- OV-3 Small intestine 4.0 7.5 Uterus 2.5 19.6 Colon ca.SW480 0.0 0.1 Placenta 3.7 4.3 Colon ca.* 0.0 0.2 Prostate 4.5 8.4SW620(SW480 met) Colon ca. HT29 0.0 0.2 Prostate ca.* 0.0 0.2 (bonemet)PC-3 Colon ca. HCT- 0.0 0.9 Testis 0.5 3.2 116 Colon ca. CaCo-2 0.41.5 Melanoma 0.0 0.7 Hs688(A).T Colon ca. 0.9 3.0 Melanoma* 0.0 0.0tissue(ODO3866) (met) Hs688(B).T Colon ca. HCC- 0.5 2.4 Melanoma 0.0 0.42998 UACC-62 Gastric ca.* (liver 0.0 0.6 Melanoma 0.0 0.2 met) NCI-N87M14 Bladder 0.0 2.7 Melanoma 0.0 0.6 LOX IMVI Trachea 2.4 6.6 Melanoma*0.0 0.6 (met) SK- MEL-5 Kidney 9.6 37.9 Adipose 7.2 15.3

[0838] TABLE DE Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag1677, Run Ag1677,Run Tissue Name 152570595 Tissue Name 152570595 Normal Colon 63.3 KidneyMargin 26.6 8120608 CC Well to Mod Diff 0.5 Kidney Cancer 2.3 (ODO3866)8120613 CC Margin (ODO3866) 77.9 Kidney Margin 50.0 8120614 CC Gr.2rectosigmoid 5.3 Kidney Cancer 0.7 (ODO3868) 9010320 CC Margin (ODO3868)2.2 Kidney Margin 26.2 9010321 CC Mod Diff (ODO3920) 29.5 Normal Uterus0.6 CC Margin (ODO3920) 100.0 Uterus Cancer 064011 1.9 CC Gr.2 ascendcolon 30.6 Normal Thyroid 21.9 (ODO3921) CC Margin (ODO3921) 42.9Thyroid Cancer 0.6 064010 CC from Partial 1.0 Thyroid Cancer 1.1Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 0.0 ThyroidMargin 14.5 A302153 Colon mets to lung 1.5 Normal Breast 6.6(OD04451-01) Lung Margin (OD04451- 15.5 Breast Cancer 0.1 02) (OD04566)Normal Prostate 6546-1 3.3 Breast Cancer 0.6 (OD04590-01) ProstateCancer 1.8 Breast Cancer Mets 5.1 (OD04410) (OD04590-03) Prostate Margin1.4 Breast Cancer 0.7 (OD04410) Metastasis (OD04655-05) Prostate Cancer0.5 Breast Cancer 064006 0.1 (OD04720-01) Prostate Margin 1.3 BreastCancer 1024 5.6 (OD04720-02) Normal Lung 061010 36.3 Breast Cancer 0.39100266 Lung Met to Muscle 0.1 Breast Margin 0.7 (ODO4286) 9100265Muscle Margin 2.7 Breast Cancer 0.3 (ODO4286) A209073 Lung MalignantCancer 6.1 Breast Margin A2090734 1.3 (OD03126) Lung Margin (OD03126)63.7 Normal Liver 0.0 Lung Cancer (OD04404) 3.5 Liver Cancer 064003 0.1Lung Margin (OD04404) 17.3 Liver Cancer 1025 0.0 Lung Cancer (OD04565)0.0 Liver Cancer 1026 0.0 Lung Margin (OD04565) 21.3 Liver Cancer 6004-T0.2 Lung Cancer (OD04237- 0.2 Liver Tissue 6004-N 0.0 01) Lung Margin(OD04237- 17.9 Liver Cancer 6005-T 0.2 02) Ocular Mel Met to Liver 0.1Liver Tissue 6005-N 0.0 (ODO4310) Liver Margin (ODO4310) 0.0 NormalBladder 1.3 Melanoma Mets to Lung 0.1 Bladder Cancer 1023 0.0 (OD04321)Lung Margin (OD04321) 33.9 Bladder Cancer 0.0 A302173 Normal Kidney 18.4Bladder Cancer 0.2 (OD04718-01) Kidney Ca, Nuclear grade 2 0.8 BladderNormal 0.6 (OD04338) Adjacent (OD04718- 03) Kidney Margin 19.3 NormalOvary 2.3 (OD04338) Kidney Ca Nuclear grade 0.1 Ovarian Cancer 0.0 1/2(OD04339) 064008 Kidney Margin 50.7 Ovarian Cancer 0.6 (OD04339)(OD04768-07) Kidney Ca, Clear cell 14.9 Ovary Margin 0.1 type (OD04340)(OD04768-08) Kidney Margin 34.4 Normal Stomach 1.9 (OD04340) Kidney Ca,Nuclear grade 3 0.3 Gastric Cancer 0.2 (OD04348) 9060358 Kidney Margin13.9 Stomach Margin 0.8 (OD04348) 9060359 Kidney Cancer 0.2 GastricCancer 0.1 (OD04622-01) 9060395 Kidney Margin 4.8 Stomach Margin 1.2(OD04622-03) 9060394 Kidney Cancer 0.0 Gastric Cancer 3.9 (OD04450-01)9060397 Kidney Margin 15.0 Stomach Margin 0.5 (OD04450-03) 9060396Kidney Cancer 8120607 0.1 Gastric Cancer 0.1 064005

[0839] TABLE DF Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag1677, Run Ag1677,Run Tissue Name 152571252 Tissue Name 152571252 Secondary Th1 act 0.0HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 SecondaryTr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVECTNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 1.0 Secondary Tr1rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 LungMicrovascular EC 0.0 TNF alpha + IL-1beta Primary Th2 act 0.0Microvascular Dermal EC 0.5 none Primary Tr1 act 0.0 MicrosvasularDermal EC 0.0 TNF alpha + IL-1beta Primary Th1 rest 0.0 Bronchialepithelium 0.0 TNF alpha + IL1beta Primary Th2 rest 0.0 Small airwayepithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 0.0 TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0 lymphocyteact CD45RO CD4 0.0 Coronery artery SMC 0.0 lymphocyte act TNF alpha +IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 Secondary CD8 0.0Astrocytes TNF alpha + 0.8 lymphocyte rest IL-1beta Secondary CD8 0.0KU-812 (Basophil) rest 1.4 lymphocyte act CD4 lymphocyte none 0.0 KU-812(Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106(Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 0.0 CCD1106(Keratinocytes) 0.0 TNF alpha + IL-1beta LAK cells IL-2 0.0 Livercirrhosis 0.0 LAK cells IL-2 + IL-12 0.0 Lupus kidney 10.5 LAK cellsIL-2 + IFN 0.4 NCI-H292 none 0.0 gamma LAK cells IL-2 + IL-18 0.0NCI-H292 IL-4 0.0 LAK cells 0.0 NCI-H292 IL-9 0.0 PMA/ionomycin NK CellsIL-2 rest 0.0 NCI-H292 IL-13 0.0 Two Way MLR 3 day 0.0 NCI-H292 IFNgamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 0.0PBMC PWM 0.0 Lung fibroblast TNF 0.0 alpha + IL-1beta PBMC PHA-L 0.0Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.8 Lung fibroblast IL-90.0 Ramos (B cell) 0.4 Lung fibroblast IL-13 0.0 ionomycin B lymphocytesPWM 0.0 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 0.0 Dermalfibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast0.0 0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0PMA/ionomycin CCD1070 IL-1beta 0.0 Dendritic cells none 0.0 Dermalfibroblast IFN 0.0 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-45.8 Dendritic cells anti- 0.0 IBD Colitis 2 0.5 CD40 Monocytes rest 0.0IBD Crohn's 0.0 Monocytes LPS 0.0 Colon 9.7 Macrophages rest 0.0 Lung14.1 Macrophages LPS 0.0 Thymus 100.0 HUVEC none 0.0 Kidney 3.9 HUVECstarved 0.0

[0840] CNS_neurodegeneration_v1.0 Summary: Ag1677 No change ofexpression of the CG55936-01 gene is noted in Alzheimer's disease,consistent with the scientific literature. However, this panel doesconfirm expression of this gene in the brain. Please see Panel 1.3D fordiscussion of utility of this gene in the central nervous system.

[0841] General_screening_panel_v1.4 Summary: Ag1677 Highest expressionof the CG55936-01 gene in this panel is seen in the cerebellum(CT=26.2), with expression also seen across all brain areas representedin this panel. This expression profile is consistent with the brainexpression seen in the CNS_neurodegeneration_v1.0 panel. Please seePanel 1.3D for discussion of utility of this gene in the central nervoussystem.

[0842] Overall, this gene is expressed in normal tissues, with muchlower expression in most cancer cell lines. This suggests that loss ofexpression of this gene might be required for the proliferation of thesecancer cell lines. A moderate level of expression is seen in a lungcancer and two breast cancer cell lines. Thus, the loss of expressionmight be used as a diagnostic marker for most cancers, except the cancertissues from which the lung and breast cancer cell lines were derived.In addition, the protein product of this gene might be of use in thetreatment of these cancers.

[0843] This gene is also moderately expressed in a wide variety ofmetabolic tissues including pancreas, adrenal, thyroid, pituitary, adultand fetal heart, adult and fetal skeletal muscle, adult and fetal liver,and adipose. Carbonic anhydrase III is reduced in adipose tissue inseveral animal models of genetic obesity. Thus, an activator of thisgene product could potentially be a drug treatment for the preventionand/or treatment of obesity in humans.

[0844] In addition, this gene is expressed at higher levels in fetallung (CT=26.5) than in adult lung (CT=31.3). Thus, expression of thisgene could be used to differentiate between fetal and adult lung tissue.The expression of this gene at significant levels in the lung isconsistent with published reports (see references below.) This suggeststhat the gene product is involved in the homeostasis of the lung.Therefore, therapeutic modulation of the expression or function of theprotein encoded by this gene could be effective in treating disease thataffect the lung or its function.

[0845] Panel 1.3D Summary: Ag1677 The expression of the CG55936-01 genewas assessed in two independent runs on this panel and there appears tobe good concordance between runs. Overall, this gene is expressed innormal tissues, with much lower expression in most cancer cell lines.Highest expression of the gene in this panel is seen in the lung(CTs=28). This significant expression in the lung is consistent with theresults in General_screening_panel_v1.4 and suggests that this geneproduct is involved in the homeostasis of this organ. The higherassociation of this gene with normal tissues suggests that loss ofexpression of this gene might be required for the proliferation of thecancer cell lines in this panel. Thus, this loss of expression might beused as a diagnostic marker for cancer.

[0846] As in the previous panel, this gene is widely expressed in avariety of metabolic tissues including pancreas, adrenal, thyroid,pituitary, adult and fetal heart, adult and fetal skeletal muscle, andadipose. Thus, this gene product may be a small molecule target for thetreatment of metabolic disease, including Types 1 and 2 diabetes.

[0847] This gene encodes a homolog of carbonic anhydrase, which is aknown marker for oligodendroglia. Carbonic anhydrase expression in thebrain is useful for distinguishing between neurons and oligodendroglia.Thus, this gene product may utility in monitoring the progression ofdiseases that involve the myelinating function of oligodendroglia, suchas Multiple Sclerosis and Alzheimer's disease.

[0848] Panel 2D Summary: Ag1677 As in the previous panels, expression ofthe CG55936-01 gene is more highly associated with normal tissues.Highest expression of the gene in this panel is seen in a normal colonsample (CT=27.8). Furthermore, expression of this gene is higher innormal colon, stomach, ovary, thyroid, kidney and lung than in thecorresponding adjacent tumor tissues. Thus, the loss of expression ofthis gene could be used to distinguish malignant colon, lung, stomach,ovary, thyroid, and kidney tissue from normal tissue from these organs.In addition, the protein product of this gene might be of use in thetreatment of these cancers.

[0849] Panel 4D Summary: Ag1677 The CG55936-01 transcript is expressedat low but significant levels in the thymus, lung and kidney(CTs—30-35), again showing preferential expression in normal tissues.Thus, this gene or the protein it encodes could be used to detect thesetissues. Therapeutically, the protein encoded for by this transcriptcould be used for immune modulation by regulating T cell development inthe thymus.

[0850] E. CG55784-01: neural cell adhesion molecule related protein(NOV5) Expression of gene CG55784-01 was assessed using the primer-probeset Ag2844, described in Table EA. Results of the RTQ-PCR runs are shownin Tables EB, EC, ED, and EE. TABLE EA Probe Name Ag2844 PrimersSequences Start Position SEQ ID NO Forward 5′-ctttccactgctctgcaaag-3′113 287 Probe TET-5′-aacccagctgtcacccagtacaggtg-3′-TAMRA 136 288 Reverse5′-gtcctgtacacctctccagatg-3′ 191 289

[0851] TABLE EB CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag2844, Rel.Exp. (%) Ag2844, Tissue Name Run 208699693 Tissue Name Run 208699693 AD1 Hippo 15.1 Control (Path) 3 2.6 Temporal Ctx AD 2 Hippo 29.1 Control(Path) 4 21.5 Temporal Ctx AD 3 Hippo 3.6 AD 1 Occipital Ctx 8.8 AD 4Hippo 7.3 AD 2 Occipital Ctx 0.0 (Missing) AD 5 hippo 45.7 AD 3Occipital Ctx 3.3 AD 6 Hippo 22.5 AD 4 Occipital Ctx 24.0 Control 2Hippo 32.5 AD 5 Occipital Ctx 12.2 Control 4 Hippo 7.7 AD 6 OccipitalCtx 55.9 Control (Path) 3 3.4 Control 1 Occipital 1.1 Hippo Ctx AD 1Temporal Ctx 15.1 Control 2 Occipital 40.6 Ctx AD 2 Temporal Ctx 30.4Control 3 Occipital 12.1 Ctx AD 3 Temporal Ctx 4.7 Control 4 Occipital5.6 Ctx AD 4 Temporal Ctx 25.9 Control (Path) 1 59.5 Occipital Ctx AD 5Inf Temporal 100.0 Control (Path) 2 5.5 Ctx Occipital Ctx AD 5SupTemporal 35.4 Control (Path) 3 0.7 Ctx Occipital Ctx AD 6 InfTemporal 28.5 Control (Path) 4 6.0 Ctx Occipital Ctx AD 6 Sup Temporal23.7 Control 1 Parietal 5.2 Ctx Ctx Control 1 Temporal 3.4 Control 2Parietal 37.4 Ctx Ctx Control 2 Temporal 48.6 Control 3 Parietal 14.3Ctx Ctx Control 3 Temporal 13.4 Control (Path) 1 59.5 Ctx Parietal CtxControl 4 Temporal 6.5 Control (Path) 2 16.6 Ctx Parietal Ctx Control(Path) 1 77.9 Control (Path) 3 2.3 Temporal Ctx Parietal Ctx Control(Path) 2 37.6 Control (Path) 4 27.0 Temporal Ctx Parietal Ctx

[0852] TABLE EC Panel 1.3D Rel. Exp. (%) Ag2844, Rel. Exp. (%) Ag2844,Tissue Name Run 167819099 Tissue Name Run 167819099 Liver adenocarcinoma0.0 Kidney (fetal) 1.3 Pancreas 0.3 Renal ca. 786-0 0.2 Pancreatic ca.CAPAN 2 0.0 Renal ca. A498 4.1 Adrenal gland 1.2 Renal ca. RXF 393 16.7Thyroid 0.2 Renal ca. ACHN 28.5 Salivary gland 0.5 Renal ca. UO-31 0.4Pituitary gland 0.0 Renal ca. TK-10 0.0 Brain (fetal) 68.3 Liver 0.0Brain (whole) 80.1 Liver (fetal) 0.0 Brain (amygdala) 43.5 Liver ca. 0.0(hepatoblast) HepG2 Brain (cerebellum) 44.8 Lung 0.0 Brain (hippocampus)42.6 Lung (fetal) 0.9 Brain (substantia nigra) 34.4 Lung ca. (smallcell) 0.0 LX-1 Brain (thalamus) 63.7 Lung ca. (small cell) 7.8 NCI-H69Cerebral Cortex 100.0 Lung ca. (s.cell var.) 0.0 SHP-77 Spinal cord 17.2Lung ca. (large 0.0 cell)NCI-H460 glio/astro U87-MG 0.0 Lung ca.(non-sm. 2.3 cell) A549 glio/astro U-118-MG 2.8 Lung ca. (non-s.cell)0.0 NCI-H23 astrocytoma SW1783 10.6 Lung ca. (non-s.cell) 1.2 HOP-62neuro*; met SK-N-AS 2.1 Lung ca. (non-s.cl) 0.0 NCI-H522 astrocytomaSF-539 0.2 Lung ca. (squam.) 0.0 SW 900 astrocytoma SNB-75 1.0 Lung ca.(squam.) 23.8 NCI-H596 glioma SNB-19 2.4 Mammary gland 0.6 glioma U2516.8 Breast ca.* (pl.ef) 0.0 MCF-7 glioma SF-295 0.0 Breast ca.* (pl.ef)0.0 MDA-MB-231 Heart (fetal) 1.2 Breast ca.* (pl.ef) 0.0 T47D Heart 0.7Breast ca. BT-549 0.0 Skeletal muscle (fetal) 0.5 Breast ca. MDA-N 0.0Skeletal muscle 0.5 Ovary 0.0 Bone marrow 0.0 Ovarian ca. OVCAR-3 0.0Thymus 0.0 Ovarian ca. OVCAR-4 0.0 Spleen 0.0 Ovarian ca. OVCAR-5 5.6Lymph node 0.3 Ovarian ca. OVCAR-8 0.0 Colorectal 0.4 Ovarian ca.IGROV-1 0.0 Stomach 0.0 Ovarian ca.* (ascites) 0.0 SK-OV-3 Smallintestine 1.3 Uterus 0.0 Colon ca. SW480 0.0 Placenta 0.0 Colon ca.* 0.0Prostate 0.2 SW620(SW480 met) Colon ca. HT29 0.0 Prostate ca.* (bone 0.0met)PC-3 Colon ca. HCT-116 0.0 Testis 0.0 Colon ca. CaCo-2 0.0 Melanoma7.9 Hs688(A).T Colon ca. 0.5 Melanoma* (met) 2.6 tissue(ODO3866)Hs688(B).T Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca.*(liver met) 0.0 Melanoma M14 0.0 NCI-N87 Bladder 0.2 Melanoma LOX 0.0IMVI Trachea 0.0 Melanoma* (met) 0.0 SK-MEL-5 Kidney 0.0 Adipose 0.6

[0853] TABLE ED Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2844, Run Ag2844,Run Tissue Name 164299480 Tissue Name 164299480 Secondary Th1 act 0.0HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 SecondaryTr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVECTNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 LungMicrovascular EC 0.0 TNF alpha + IL-1beta Primary Th2 act 0.0Microvascular Dermal EC 0.0 none Primary Tr1 act 0.0 MicrosvasularDermal EC 0.0 TNF alpha + IL-1beta Primary Th1 rest 0.0 Bronchialepithelium 0.0 TNF alpha + IL1beta Primary Th2 rest 0.0 Small airwayepithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 0.0 TNFalpha + IL-1beta CD45RA CD4 43.5 Coronery artery SMC rest 1.7 lymphocyteact CD45RO CD4 0.0 Coronery artery SMC 5.1 lymphocyte act TNF alpha +IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 2.0 Secondary CD8 0.0Astrocytes TNF alpha + 3.7 lymphocyte rest IL-1beta Secondary CD8 0.0KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 0.0 KU-812(Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106(Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 0.0 CCD1106(Keratinocytes) 0.0 TNF alpha + IL-1beta LAK cells IL-2 0.0 Livercirrhosis 0.3 LAK cells IL-2 + IL-12 0.0 Lupus kidney 0.0 LAK cellsIL-2 + IFN 0.0 NCI-H292 none 1.8 gamma LAK cells IL-2 + IL-18 0.0NCI-H292 IL-4 27.2 LAK cells 0.0 NCI-H292 IL-9 3.7 PMA/ionomycin NKCells IL-2 rest 0.0 NCI-H292 IL-13 17.8 Two Way MLR 3 day 0.0 NCI-H292IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 4.3PBMC PWM 0.0 Lung fibroblast TNF 3.4 alpha + IL-1beta PBMC PHA-L 0.0Lung fibroblast IL-4 12.5 Ramos (B cell) none 0.0 Lung fibroblast IL-92.6 Ramos (B cell) 0.0 Lung fibroblast IL-13 5.3 ionomycin B lymphocytesPWM 0.0 Lung fibroblast IFN 5.2 gamma B lymphocytes CD40L 0.0 Dermalfibroblast 90.1 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast100.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 39.8PMA/ionomycin CCD1070 IL-1beta Dendritic cells none 0.0 Dermalfibroblast IFN 1.6 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-44.5 Dendritic cells anti- 0.0 IBD Colitis 2 0.0 CD40 Monocytes rest 0.0IBD Crohn's 0.2 Monocytes LPS 0.0 Colon 1.3 Macrophages rest 0.0 Lung0.0 Macrophages LPS 0.0 Thymus 0.4 HUVEC none 0.0 Kidney 0.5 HUVECstarved 0.0

[0854] TABLE EF Panel CNS_1 Rel. Exp. (%) Ag2844, Rel. Exp. (%) Ag2844,Tissue Name Run 171669549 Tissue Name Run 171669549 BA4 Control 27.4BA17 PSP 23.7 BA4 Control2 37.9 BA17 PSP2 8.0 BA4 9.8 Sub Nigra Control36.3 Alzheimer's2 BA4 Parkinson's 32.1 Sub Nigra Control2 49.7 BA4 33.2Sub Nigra 10.7 Parkinson's2 Alzheimer's2 BA4 28.7 Sub Nigra 56.3Huntington's Parkinson's2 BA4 8.8 Sub Nigra 66.4 Huntington's2Huntington's BA4 PSP 6.3 Sub Nigra 17.0 Huntington's2 BA4 PSP2 15.2 SubNigra PSP2 7.6 BA4 Depression 18.9 Sub Nigra 5.4 Depression BA4 6.4 SubNigra 6.4 Depression2 Depression2 BA7 Contro1 58.6 Glob Palladus 20.3Control BA7 Control2 18.7 Glob Palladus 34.9 Control2 BA7 6.4 GlobPalladus 10.2 Alzheimer's2 Alzheimer's BA7 Parkinson's 18.8 GlobPalladus 9.6 Alzheimer's2 BA7 44.1 Glob Palladus 100.0 Parkinson's2Parkinson's BA7 66.9 Glob Palladus 25.9 Huntington's2 Parkinson's2 BA725.2 Glob Palladus PSP 3.7 Huntington's2 BA7 PSP 48.6 Glob Palladus PSP214.5 BA7 PSP2 34.2 Glob Palladus 9.7 Depression BA7 Depression 6.3 TempPole Control 14.9 BA9 Control 29.3 Temp Pole Control2 60.7 BA9 Control287.1 Temp Pole 4.7 Alzheimer's BA9 Alzheimer's 4.5 Temp Pole 5.0Alzheimer's2 BA9 14.1 Temp Pole 28.5 Alzheimer's2 Parkinson's BA9Parkinson's 39.0 Temp Pole 30.4 Parkinson's2 BA9 36.3 Temp Pole 45.1Parkinson's2 Huntington's BA9 48.0 Temp Pole PSP 0.0 Huntington's BA912.4 Temp Pole PSP2 5.4 Huntington's2 BA9 PSP 13.6 Temp Pole 5.2Depression2 BA9 PSP2 2.9 Cing Gyr Control 0.0 BA9 Depression 10.1 CingGyr Control2 36.6 BA9 8.2 Cing Gyr 15.3 Depression2 Alzheimer's BA17Control 28.7 Cing Gyr 9.9 Alzheimer's2 BA17 Control2 50.3 Cing Gyr 47.6Parkinson's BA17 5.3 Cing Gyr 40.1 Alzheimer's2 Parkinson's2 BA17 26.2Cing Gyr 58.6 Parkinson's Huntington's BA17 23.2 Cing Gyr 21.9Parkinson's2 Huntington's2 BA17 24.7 Cing Gyr PSP 11.6 Huntington's BA176.6 Cing Gyr PSP2 3.9 Huntington's2 BA17 4.7 Cing Gyr 8.0 DepressionDepression BA17 26.2 Cing Gyr 22.4 Depression2 Depression2

[0855] CNS_neurodegeneration_v1.0 Summary: Ag2844While this panel showsno specific Alzheimer's association with the CG55784-01 gene, theseresults confirm expression of this gene in the brain. See Panel 1.3D fordiscussion of utility of this gene in the brain.

[0856] Panel 1.3D Summary: Ag2844 Highly brain-preferential expressionof the CG55784-01 gene indicates a specific role for this gene productin the brain. This gene encodes a protein that is homologous to a neuralcell adhesion molecule (NCAM). NCAM related proteins, such as Nr-CAM,play a critical role in neurite extension. Therefore, the introductionof ligands specific for this gene product, such as contactin, indirected brain regions may have utility in fostering focal neuriteoutgrowth. This may have utility in therapeutically countering neuritedegeneration of neurodegenerative diseases such as Alzheimer's, ataxias,and Parkinson's disease.

[0857] In addition, the expression of this gene is relatively high inthe normal brain samples compared to the cancer cell lines derived frombrain cancer. Hence, expression of this gene can be used as a marker todifferentiate between normal and cancerous tissue. There are alsosignificantly higher levels of expression in renal cancer cell linescompared to a normal kidney sample. Therefore, expression of this genemay also be used as a marker in renal cancer.

[0858] Panel 2.2 Summary: Ag2844 Expression of the CG55784-01 gene islow/undetectable in all samples on this panel (CTs>35). (Data notshown.)

[0859] Panel 4D Summary: Ag2844 The CG55784-01 transcript is induced inIL-4 and IL-13 treated NCI-H292 cells, expressed constitutively in adermal fibroblast cell line and appears to be slightly induced by IL-4in lung fibroblasts. CD45RA (naive) T cells also express the transcript.The transcript encodes an NCAM-like molecule. Based on the expressionpattern of the transcript, the homology to NCAM protein, and theregulation of transcript expression by IL-4 and IL-13, therapeuticsdesigned with the protein encoded for by this transcript may beimportant in the treatment of asthma and COPD.

[0860] Panel CNS_(—)1 Summary: Ag2844 Expression in this panel furtherconfirms widespread brain expression of the CG55784-01 gene. Please seePanel 1.3D for discussion of utility of this gene in the brain.

[0861] F. CG55916-01: phospholipase (NOV6)

[0862] Expression of gene CG55916-01 was assessed using the primer-probeset Ag2843, described in Table FA. Results of the RTQ-PCR runs are shownin Tables FB, FC, FD, FE, and FF. TABLE FA Probe Name Ag2843 PrimersSequences Start Position SEQ ID NO Forward 5′-accaatggatccactcctatct-3′544 290 Probe TET-5′-ctgactccaaccaggacagcaagatg-3′-TAMRA 574 291 Reverse5′-attctcagcaggctcttgatct-3′ 610 292

[0863] TABLE FB CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag2843, Rel.Exp. (%) Ag2843, Tissue Name Run 209058882 Tissue Name Run 209058882 AD1 Hippo 16.6 Control (Path) 3 11.0 Temporal Ctx AD 2 Hippo 33.2 Control(Path) 4 35.4 Temporal Ctx AD 3 Hippo 10.3 AD 1 Occipital Ctx 15.9 AD 4Hippo 29.9 AD 2 Occipital Ctx 0.3 (Missing) AD 5 Hippo 38.4 AD 3Occipital Ctx 11.2 AD 6 Hippo 100.0 AD 4 Occipital Ctx 19.8 Control 2Hippo 30.6 AD 5 Occipital Ctx 20.7 Control 4 Hippo 48.6 AD 6 OccipitalCtx 18.6 Control (Path) 3 9.5 Control 1 Occipital 9.2 Hippo Ctx AD 1Temporal Ctx 24.1 Control 2 Occipital 34.2 Ctx AD 2 Temporal Ctx 20.0Control 3 Occipital 17.1 Ctx AD 3 Temporal Ctx 8.8 Control 4 Occipital18.2 Ctx AD 4 Temporal Ctx 12.1 Control (Path) 1 45.1 Occipital Ctx AD 5Inf Temporal 37.4 Control (Path) 2 18.3 Ctx Occipital Ctx AD 5 SupTemporal 38.7 Control (Path) 3 6.7 Ctx Occipital Ctx AD 6 Inf Temporal64.2 Control (Path) 4 21.6 Ctx Occipital Ctx AD 6 Sup Temporal 59.0Control 1 Parietal 13.8 Ctx Ctx Control 1 Temporal 7.0 Control 2Parietal 33.9 Ctx Ctx Control 2 Temporal 16.7 Control 3 Parietal 11.9Ctx Ctx Control 3 Temporal 11.7 Control (Path) 1 30.1 Ctx Parietal CtxControl 3 Temporal 25.9 Control (Path) 2 18.9 Ctx Parietal Ctx Control(Path) 1 26.6 Control (Path) 3 9.0 Temporal Ctx Parietal Ctx Control(Path) 2 23.5 Control (Path) 4 40.6 Temporal Ctx Parietal Ctx

[0864] TABLE FC Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2843, Run Ag2843, Run Ag2843, Run Ag2843, Run TissueName 161560324 165721033 Tissue Name 161560324 165721033 Liver 74.2 65.1Kidney (fetal) 4.7 3.1 adenocarcinoma Pancreas 0.4 1.4 Renal ca. 786-06.6 7.6 Pancreatic ca. 18.2 49.7 Renal ca. 39.2 56.3 CAPAN 2 A498Adrenal gland 5.1 12.4 Renal ca. RXF 1.9 9.3 393 Thyroid 3.8 5.4 Renalca. 19.5 39.0 ACHN Salivary gland 0.5 2.0 Renal ca. UO- 16.4 30.6 31Pituitary gland 1.9 6.2 Renal ca. TK- 7.4 8.4 10 Brain (fetal) 2.3 9.3Liver 0.0 0.9 Brain (whole) 9.3 23.3 Liver (fetal) 0.1 0.8 Brain(amygdala) 16.5 29.7 Liver ca. 12.6 33.2 (hepatoblast) HepG2 Brain(cerebellum) 9.7 25.0 Lung 2.2 5.0 Brain 22.4 41.8 Lung (fetal) 1.4 2.2(hippocampus) Brain (substantia 4.4 16.5 Lung ca. 19.8 84.1 nigra)(small cell) LX-1 Brain (thalamus) 17.3 54.0 Lung ca. 0.2 0.4 (smallcell) NCI-H69 Cerebral Cortex 40.6 18.7 Lung ca. 0.8 0.7 (s. cell var.)SHP-77 Spinal cord 46.7 58.6 Lung ca. (large 14.3 59.0 cell)NCI-H460glio/astro U87-MG 13.2 9.0 Lung ca. (non- 16.7 28.1 sm. cell) A549glio/astro U-118- 6.7 34.2 Lung ca. (non- 2.1 1.8 MG s. cell) NCI- H23astrocytoma 16.7 17.7 Lung ca. (non- 10.8 27.9 SW1783 s. cell) HOP-62neuro*; met SK-N- 7.6 21.5 Lung ca. (non 11.3 13.0 AS s. cl) NCI- H522astrocytoma SF- 7.7 11.8 Lung ca. 1.0 0.2 539 (squam.) SW 900astrocytoma SNB- 4.1 18.2 Lung ca. 0.3 0.3 75 (squam.) NCI- H596 gliomaSNB-19 19.3 24.3 Mammary 4.4 6.2 gland glioma U251 7.4 21.6 Breast ca.*5.6 11.2 (pl. ef) MCF-7 glioma SF-295 23.3 26.6 Breast ca.* 13.2 52.9(pl. ef) MDA- MB-231 Heart (fetal) 24.5 9.0 Breast ca.* 7.5 15.3 (pl.ef) T47D Heart 17.3 15.4 Breast ca. BT- 2.6 11.0 549 Skeletal muscle100.0 20.0 Breast ca. 2.3 2.6 (fetal) MDA-N Skeletal muscle 61.6 100.0Ovary 31.6 7.5 Bone marrow 0.2 0.9 Ovarian ca. 32.1 68.3 OVCAR-3 Thymus2.6 0.4 Ovarian ca. 7.9 39.0 OVCAR-4 Spleen 1.4 1.4 Ovarian ca. 17.036.6 OVCAR-5 Lymph node 0.7 1.7 Ovarian ca. 29.9 24.1 OVCAR-8 Colorectal36.9 18.8 Ovarian ca. 4.7 6.8 IGROV-1 Stomach 4.2 13.0 Ovarian ca.* 47.099.3 (ascites) SK- OV-3 Small intestine 2.4 8.9 Uterus 2.9 15.1 Colonca. SW480 15.9 28.9 Placenta 6.5 6.6 Colon ca.* 14.9 16.8 Prostate 4.85.2 SW620(SW480 met) Colon ca. HT29 38.4 17.2 Prostate ca.* 27.5 86.5(bone met)PC-3 Colon ca. HCT- 15.1 28.1 Testis 12.3 17.3 116 Colon ca.CaCo-2 25.2 19.6 Melanoma 8.8 3.5 Hs688(A).T Colon ca. 37.9 26.1Melanoma* 14.4 15.6 tissue(ODO3866) (met) Hs688(B).T Colon ca. HCC- 15.620.3 Melanoma 1.9 6.5 2998 UACC-62 Gastric ca.* (liver 44.4 62.4Melanoma 1.0 7.5 met) NCI-N87 M14 Bladder 8.9 6.3 Melanoma 6.0 9.0 LOXIMVI Trachea 11.5 13.8 Melanoma* 1.3 3.7 (met) SK- MEL-5 Kidney 4.1 2.4Adipose 4.6 5.6

[0865] TABLE FD Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2843, Run Ag2843,Tissue Name 161590185 Tissue Name Run 161590185 Normal Colon 70.7 KidneyMargin 4.3 8120608 CC Well to Mod Diff 30.6 Kidney Cancer 1.0 (ODO3866)8120613 CC Margin (ODO3866) 30.6 Kidney Margin 7.3 8120614 CC Gr.2rectosigmoid 17.1 Kidney Cancer 18.6 (ODO3868) 9010320 CC Margin(ODO3868) 5.9 Kidney Margin 11.4 9010321 CC Mod Diff (ODO3920) 12.7Normal Uterus 6.0 CC Margin (ODO3920) 48.0 Uterus Cancer 064011 6.7 CCGr.2 ascend colon 31.4 Normal Thyroid 7.4 (ODO3921) CC Margin (ODO3921)19.8 Thyroid Cancer 66.9 064010 CC from Partial 17.8 Thyroid Cancer 19.5Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 0.3 ThyroidMargin 4.8 A302153 Colon mets to lung 15.0 Normal Breast 11.7(OD04451-01) Lung Margin (OD04451- 4.6 Breast Cancer 0.2 02) (OD04566)Normal Prostate 6546-1 6.2 Breast Cancer 59.5 (OD04590-01) ProstateCancer 6.3 Breast Cancer Mets 33.2 (OD04410) (OD04590-03) ProstateMargin 9.6 Breast Cancer 14.4 (OD04410) Metastasis (OD04655-05) ProstateCancer 18.2 Breast Cancer 064006 6.7 (OD04720-01) Prostate Margin 16.7Breast Cancer 1024 14.5 (OD04720-02) Normal Lung 061010 8.1 BreastCancer 9.9 9100266 Lung Met to Muscle 17.7 Breast Margin 6.0 (ODO4286)9100265 Muscle Margin 32.1 Breast Cancer 10.4 (ODO4286) A209073 LungMalignant Cancer 12.2 Breast Margin 16.3 (OD03126) A2090734 Lung Margin(OD03126) 7.3 Normal Liver 1.4 Lung Cancer (OD04404) 7.6 Liver Cancer064003 0.6 Lung Margin (OD04404) 12.2 Liver Cancer 1025 0.6 Lung Cancer(OD04565) 16.0 Liver Cancer 1026 2.3 Lung Margin (OD04565) 7.9 LiverCancer 6004-T 1.0 Lung Cancer (OD04237- 0.6 Live Tissue 6004-N 2.3 01)Lung Margin (OD04237- 6.3 Liver Cancer 6005-T 3.1 02) Ocular Mel Met toLiver 7.5 Liver Tissue 6005-N 0.2 (ODO4310) Liver Margin (ODO4310) 0.3Normal Bladder 10.6 Melanoma Mets to Lung 3.3 Bladder Cancer 1023 13.4(OD04321) Lung Margin (OD04321) 15.0 Bladder Cancer 3.2 A302173 NormalKidney 7.6 Bladder Cancer 27.7 (OD04718-01) Kidney Ca, Nuclear grade 226.6 Bladder Normal 15.0 (OD04338) Adjacent (OD04718- 03) Kidney Margin8.1 Normal Ovary 11.7 (OD04338) Kidney Ca Nuclear grade 100.0 OvarianCancer 73.2 1/2 (OD04339) 064008 Kidney Margin 6.7 Ovarian Cancer 4.8(OD04339) (OD04768-07) Kidney Ca, Clear cell 26.6 Ovary Margin 8.1 type(OD04340) (OD04768-08) Kidney Margin 11.4 Normal Stomach 26.4 (OD04340)Kidney Ca, Nuclear grade 3 7.7 Gastric Cancer 4.1 (OD04348) 9060358Kidney Margin 7.3 Stomach Margin 13.1 (OD04348) 9060359 Kidney Cancer21.0 Gastric Cancer 24.3 (OD04622-01) 9060395 Kidney Margin 3.0 StomachMargin 25.3 (OD04622-03) 9060394 Kidney Cancer 21.2 Gastric Cancer 57.8(OD04450-01) 9060397 Kidney Margin 5.6 Stomach Margin 36.9 (OD04450-03)9060396 Kidney Cancer 8120607 42.3 Gastric Cancer 25.7 064005

[0866] TABLE FE Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2843, Run Ag2843,Run Tissue Name 159616571 Tissue Name 159616571 Secondary Th1 act 0.6HUVEC IL-1beta 3.8 Secondary Th2 act 1.1 HUVEC lFN gamma 5.1 SecondaryTr1 act 0.6 HUVEC TNF alpha + IFN 1.4 gamma Secondary Th1 rest 0.2 HUVECTNF alpha + IL4 2.6 Secondary Th2 rest 0.2 HUVEC IL-11 5.6 Secondary Tr1rest 0.5 Lung Microvascular EC 18.4 none Primary Th1 act 1.7 LungMicrovascular EC 6.1 TNF alpha + IL-1beta Primary Th2 act 2.4Microvascular Dermal EC 19.6 none Primary Tr1 act 0.0 MicrosvasularDermal EC 6.3 TNF alpha + IL-1beta Primary Th1 rest 0.3 Bronchialepithelium 9.9 TNF alpha + IL1beta Primary Th2 rest 1.4 Small airwayepithelium 20.7 none Primary Tr1 rest 0.3 Small airway epithelium 100.0TNF alpha + IL-1beta CD45RA CD4 6.3 Coronery artery SMC rest 6.1lymphocyte act CD45RO CD4 1.7 Coronery artery SMC 3.2 lymphocyte act TNFalpha + IL-1beta CD8 lymphocyte act 1.3 Astrocytes rest 30.1 SecondaryCD8 0.6 Astrocytes TNF alpha + 22.7 lymphocyte rest IL-1beta SecondaryCD8 0.4 KU-812 (Basophil) rest 0.6 lymphocyte act CD4 lymphocyte none0.2 KU-812 (Basophil) 2.6 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0CCD1106 (Keratinocytes) 27.7 CD95 CH11 none LAK cells rest 0.3 CCD1106(Keratinocytes) 4.9 TNF alpha + IL-1beta LAK cells IL-2 0.9 Livercirrhosis 1.1 LAK cells IL-2+IL-12 0.9 Lupus kidney 2.3 LAK cellsIL-2+IFN 0.3 NCI-H292 none 48.3 gamma LAK cells IL-2+IL-18 0.2 NCI-H292IL-4 57.8 LAK cells 0.7 NCI-H292 IL-9 69.3 PMA/ionomycin NK Cells IL-2rest 0.7 NCI-H292 IL-13 47.0 Two Way MLR 3 day 0.6 NCI-H292 IFN gamma42.6 Two Way MLR 5 day 0.4 HPAEC none 13.7 Two Way MLR 7 day 0.7 HPAECTNF alpha + IL- 2.1 1beta PBMC rest 1.2 Lung fibroblast none 32.3 PBMCPWM 2.9 Lung fibroblast TNF alpha + 10.1 IL-1beta PBMC PHA-L 0.7 Lungfibroblast IL-4 31.9 Ramos (B cell) none 0.4 Lung fibroblast IL-9 32.3Ramos (B cell) 1.1 Lung fibroblast IL-13 24.0 ionomycin B lymphocytesPWM 2.7 Lung fibroblast IFN 37.4 gamma B lymphocytes CD40L 0.6 Dermalfibroblast 18.2 and IL-4 CCD1070 rest EOL-1 dbcAMP 1.9 Dermal fibroblast12.9 CCD1070 TNF alpha EOL-1 dbcAMP 8.6 Dermal fibroblast 9.9PMA/ionomycin CCD1070 IL-1beta Dendritic cells none 0.0 Dermalfibroblast IFN 29.9 gamma Dendritic cells LPS 0.1 Dermal fibroblast IL-436.1 Dendritic cells anti- 0.8 IBD Colitis 2 1.3 CD40 Monocytes rest 0.7IBD Crohn's 0.8 Monocytes LPS 0.4 Colon 5.4 Macrophages rest 1.3 Lung5.2 Macrophages LPS 0.3 Thymus 6.7 HUVEC none 11.1 Kidney 2.3 HUVECstarved 15.2

[0867] TABLE FF Panel 5D Rel. Exp. (%) Rel. Exp. (%) Ag2843, Run Ag2843,Run Tissue Name 170221175 Tissue Name 170221175 97457_Patient- 26.694709_Donor 2 AM - A_adipose 19.5 02go_adipose 97476_Patient- 5.594710_Donor 2 AM - B_adipose 10.3 07sk_skeletal muscle 97477_Patient-14.0 94711_Donor 2 AM - C_adipose 6.3 07ut_uterus 97478_Patient- 17.494712_Donor 2 AD - A_adipose 39.5 07pl_placenta 97481_Patient- 4.494713_Donor 2 AD - B_adipose 37.1 08sk_skeletal muscle 97482_Patient-14.8 94714_Donor 2 AD - C_adipose 28.3 08ut_uterus 97483_Patient- 15.394742_Donor 3 U - 18.8 08pl_placenta A_Mesenchymal Stem Cells97486_Patient- 8.4 94743_Donor 3 U - 24.5 09sk_skeletal muscleB_Mesenchymal Stem Cells 97487_Patient- 9.3 94730_Donor 3 AM - A_adipose34.4 09ut_uterus 97488_Patient- 11.0 94731_Donor 3 AM - B_adipose 18.809pl_placenta 97492_Patient- 9.7 94732_Donor 3 AM - C_adipose 20.010ut_uterus 97493_Patient- 24.3 94733_Donor 3 AD - A_adipose 28.510pl_placenta 97495_Patient- 7.5 94734_Donor 3 AD - B_adipose 17.211go_adipose 97496_Patient- 27.4 94735_Donor 3 AD - C_adipose 23.311sk_skeletal muscle 97497_Patient- 27.0 77138_Liver_HepG2untreated 71.711ut_uterus 97498_Patient- 16.4 73556_Heart_Cardiac stromal 29.511pl_placenta cells (primary) 97500_Patient- 21.5 81735_Small Intestine4.6 12go_adipose 97501_Patient- 40.9 72409_Kidney_Proximal 14.912sk_skeletal muscle Convoluted Tubule 97502_Patient- 25.2 82685_Smallintestine_Duodenum 1.6 12ut_uterus 97503_Patient- 9.290650_Adrenal_Adrenocortical 12.2 12pl_placenta adenoma 94721_Donor 2U - 26.4 72410_Kidney_HRCE 100.0 A_Mesenchymal Stem Cells 94722_Donor 2U - 21.3 72411_Kidney_HRE 79.0 B_Mesenchymal Stem Cells 94723_Donor 2U - 20.3 73139_Uterus_Uterine smooth 22.4 C_Mesenchymal Stem musclecells Cells

[0868] CNS_neurodegeneration_v1.0 Summary: Ag2843While no specificassociation between Alzheimer's disease and the CG55916-01 gene isdetected in this panel, these results confirm expression of this gene inthe brain. See Panel 1.3D for discussion of utility of this gene in thecentral nervous system.

[0869] Panel 1.3D Summary: Ag2743 Two experiments both show highestexpression of the CG55916-01 gene in both fetal and adult skeletalmuscle (CTs=27-28). This gene encodes a protein that is homologous to aphosphoinositol-specific (PI) phospholipase. It has moderate expressionin a variety of metabolic tissues including pancreas, adrenal, thyroid,pituitary, adult and fetal heart, adult and fetal liver, and adipose.PI-specific phospholipases are responsible for the generation of thesecond messengers diacylglycerol and inositol triphosphate, whichpromote the activation of protein kinase C and the release of Ca++ fromintracellular stores, respectively. Given the myriad roles that thesesecond messengers play in cellular metabolism, it is that selectiveinhibition of this gene product through the application of a smallmolecule therapeutic may be useful in the treatment of metabolicdisease, including Types 1 and 2 diabetes, and obesity.

[0870] In addition, all the cancer cell lines on this panel express thisgene, suggesting that this gene plays an important role in proliferatingcells. There is increased expression in some colon, kidney, lung,breast, ovary, prostate and pancreatic cancer cell lines compared to thenormal tissues suggesting that this gene can be used as a marker todifferentiate malignant and normal tissue.

[0871] Furthermore, expression of this gene in the brain supportsabundant literature documenting an important and broad role for PLC inneurons. Dysregulation of PLC in the brain of schizophrenics suggeststhat specific modulators of this gene product may have utility indamping and thus influencing schizophrenia. Decreased PLC enzymaticactivity in Alzheimer's disease suggests that agents that specificallyinduce the activity of the protein encoded by this gene may also haveutility in treating Alzheimer's disease.

[0872] Panel 2D Summary: Ag2843 The CG55916-01 gene encodes a putativemember of the phospholipase family and is moderately expressed in alltissues on this panel. The highest expression is seen in a kidney cancersample (CT=26.8). There are significantly higher level of expression inthyroid, kidney and metastatic breast cancers compared to normaladjacent tissues. These data indicate that the expression of this genemight be associated with these forms of cancer and that therapeuticmodulation of this gene using small molecule inhibitors might be of usein the treatment of these cancers.

[0873] Panel 4D Summary: Ag2843 The CG55916-01 transcript is expressedin most tissues on this panel, but is highly expressed in activatedsmall airway epithelium (CT=25.8). The transcript encodes a putativeprotein involved in signal transduction. Designing protein therapeuticsthat inhibit the expression of the transcript or the function of theprotein could be important in the treatment of inflammatory diseases,and particularly ones that involve the small airway epithelium such asasthma.

[0874] Panel 5D Summary: Ag2843 The CG55916-01 gene is moderatelyexpressed in adipose, placenta, and skeletal muscle, results that areconsistent with the expression in Panel 1.3D. This gene is alsoexpressed in human mesenchymal stem cells that can be differentiated invitro into adipocytes, chondrocytes and osteocytes. Thus, this geneproduct may be a small molecule target for the treatment of disease inbone, cartilage, and adipose.

[0875] G. CG55802-01: 3 ALPHA-HYDROXYSTEROIID DEHYDROGENASE-LIKE (NOV7)

[0876] Expression of gene CG55802-01 was assessed using the primer-probeset Ag2624, described in Table GA. TABLE GA Probe Name Ag2624 PrimersSequences Start Position SEQ ID NO Forward 5′-ttgagttgactccagaggacat-3′887 293 Probe TET-5′-attgatggcctcaacagaaatctccg-3′-TAMRA 916 294 Reverse5′-ccagcaagactgaagaaagaaa-3′ 947 295

[0877] CNS_neurodegeneration_v1.0 Summary: Ag2624 Expression of theCG55802-01 gene is low/undetected in all the samples in this panel(CT>35). The amp plot suggests that there is a high probability of aprobe failure.

[0878] Panel 1.3D Summary: Ag2624 Expression of the CG55802-01 gene islow/undetected in all the samples in this panel (CT>35). The amp plotsuggests that there is a high probability of a probe failure.

[0879] Panel 4D Summary: Ag2624 Expression of the CG55802-01 gene islow/undetected in all the samples in this panel (CT>35). The amp plotsuggests that there is a high probability of a probe failure.

[0880] H. CG55906-01: S3-12 (NOV19)

[0881] Expression of gene CG55906-01 was assessed using the primer-probeset Ag2840, described in Table HA. Results of the RTQ-PCR runs are shownin Tables HB, HC, HD, HE, HF and HG. TABLE HA Probe Name Ag2840 PrimersSequences Start Position SEQ ID NO Forward 5′-tctatggtcatgggtacgaaag-3′1190 296 Probe TET-5′-acacgatgtccactgggctcacag-3′-TAMRA 1212 297 Reverse5′-gttgtgttcagcccagtttg-3′ 1265 298

[0882] TABLE HB Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Ag2840, Ag2840,Tissue Name Run 161922468 Tissue Name Run 161922468 Liver adenocarcinoma0.5 Kidney (fetal) 1.6 Pancreas 0.3 Renal ca. 786-0 0.1 Pancreatic ca.CAPAN 2 0.2 Renal ca. A498 0.2 Adrenal gland 0.6 Renal ca. RXF 393 0.0Thyroid 0.8 Renal ca. ACHN 0.0 Salivary gland 0.6 Renal ca. UO-31 0.0Pituitary gland 0.3 Renal ca. TK-10 0.0 Brain (fetal) 0.0 Liver 0.4Brain (whole) 0.2 Liver (fetal) 0.9 Brain (amygdala) 0.6 Liver ca. 0.6(hepatoblast) HepG2 Brain (cerebellum) 0.2 Lung 0.3 Brain (hippocampus)0.6 Lung (fetal) 0.2 Brain (substantia nigra) 0.1 Lung ca. (small cell)0.1 LX-1 Brain (thalamus) 0.2 Lung ca. (small cell) 0.0 NCI-H69 CerebralCortex 2.1 Lung ca. (s. cell var.) 0.1 SHP-77 Spinal cord 0.8 Lung ca.(large 0.0 cell)NCI-H460 glio/astro U87-MG 0.0 Lung ca. (non-sm. 0.1cell) A549 glio/astro U-118-MG 0.1 Lung ca. (non-s. cell) 0.0 NCI-H23astrocytoma SW1783 0.1 Lung ca. (non-s. cell) 0.0 HOP-62 neuro*; metSK-N-AS 0.0 Lung ca. (non-s. cl) 0.1 NCI-H522 astrocytoma SF-539 0.2Lung ca. (squam.) 0.1 SW 900 astrocytoma SNB-75 0.1 Lung ca. (squam.)0.0 NCI-H596 glioma SNB-19 0.0 Mammary gland 18.4 glioma U251 0.1 Breastca.* (pl. ef) 0.1 MCF-7 glioma SF-295 0.2 Breast ca.* (pl. ef) 0.0MDA-MB-231 Heart (fetal) 1.0 Breast ca.* (pl. ef) 0.2 T47D Heart 11.8Breast ca. BT-549 0.0 Skeletal muscle (fetal) 100.0 Breast ca. MDA-N 0.0Skeletal muscle 32.8 Ovary 2.9 Bone marrow 0.4 Ovarian ca. OVCAR-3 0.2Thymus 3.5 Ovarian ca. OVCAR-4 0.1 Spleen 0.4 Ovarian ca. OVCAR-5 0.4Lymph node 0.7 Ovarian ca. OVCAR-8 0.3 Colorectal 6.7 Ovarian ca.IGROV-1 0.0 Stomach 1.0 Ovarian ca.* (ascites) 0.0 SK-OV-3 Smallintestine 2.7 Uterus 1.5 Colon ca. SW480 0.0 Placenta 0.0 Colon ca.* 0.1Prostate 0.5 SW620(SW480 met) Colon ca. HT29 0.4 Prostate ca.* (bone 1.7met)PC-3 Colon ca. HCT-116 0.1 Testis 0.6 Colon ca. CaCo-2 0.0 Melanoma0.0 Hs688(A).T Colon ca. 6.4 Melanoma* (met) 0.0 tissue(ODO3866)Hs688(B).T Colon Ca. HCC-2998 0.1 Melanoma UACC-62 0.0 Gastric ca.*(liver met) 0.8 Melanoma M14 0.0 NCI-N87 Bladder 3.3 Melanoma LOX 0.0IMVI Trachea 3.2 Melanoma* (met) 0.0 SK-MEL-5 Kidney 0.9 Adipose 87.1

[0883] TABLE HC Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2840, Run Ag2840,Tissue Name 161922469 Tissue Name Run 161922469 Normal Colon 41.8 KidneyMargin 0.2 8120608 CC Well to Mod Diff 4.3 Kidney Cancer 0.7 (ODO3866)8120613 CC Margin (ODO3866) 6.9 Kidney Margin 2.0 8120614 CC Gr.2rectosigmoid 1.1 Kidney Cancer 8.4 (ODO3868) 9010320 CC Margin (ODO3868)4.5 Kidney Margin 2.0 9010321 CC Mod Diff (ODO3920) 0.0 Normal Uterus2.4 CC Margin (ODO3920) 0.0 Uterus Cancer 064011 4.4 CC Gr.2 ascendcolon 0.4 Normal Thyroid 2.3 (ODO3921) CC Margin (ODO3921) 2.5 ThyroidCancer 0.0 064010 CC from Partial 0.2 Thyroid Cancer 0.4 Hepatectomy(ODO4309) A302152 Mets Liver Margin (ODO4309) 1.8 Thyroid Margin 0.5A302153 Colon mets to lung 0.1 Normal Breast 80.7 (OD04451-01) LungMargin (OD04451- 0.1 Breast Cancer 1.5 02) (OD04566) Normal Prostate6546-1 0.9 Breast Cancer 21.0 (OD04590-01) Prostate Cancer 1.2 BreastCancer Mets 100.0 (OD04410) (OD04590-03) Prostate Margin 3.2 BreastCancer 13.3 (OD04410) Metastasis (OD04655-05) Prostate Cancer 0.8 BreastCancer 064006 0.9 (OD04720-01) Prostate Margin 1.9 Breast Cancer 10245.8 (OD04720-02) Normal Lung 061010 1.4 Breast Cancer 3.2 9100266 LungMet to Muscle 0.5 Breast Margin 5.9 (ODO4286) 9100265 Muscle Margin 16.4Breast Cancer 2.0 (ODO4286) A209073 Lung Malignant Cancer 0.1 BreastMargin 7.9 (OD03126) A2090734 Lung Margin (OD03126) 0.4 Normal Liver 3.3Lung Cancer (OD04404) 0.3 Liver Cancer 064003 2.2 Lung Margin (OD04404)0.3 Liver Cancer 1025 6.0 Lung Cancer (OD04565) 0.0 Liver Cancer 10262.0 Lung Margin (OD04565) 0.2 Liver Cancer 6004-T 7.5 Lung Cancer(OD04237- 0.0 Liver Tissue 6004-N 2.2 01) Lung Margin (OD04237- 0.1Liver Cancer 6005-T 1.8 02) Ocular Mel Met to Liver 0.4 Liver Tissue6005-N 0.3 (ODO4310) Liver Margin (ODO4310) 2.6 Normal Bladder 6.0Melanoma Mets to Lung 0.0 Bladder Cancer 1023 0.7 (OD04321) Lung Margin(OD04321) 0.2 Bladder Cancer 0.4 A302173 Normal Kidney 3.1 BladderCancer 0.1 (OD04718-01) Kidney Ca, Nuclear grade 2 0.0 Bladder Normal11.7 (OD04338) Adjacent (OD04718- 03) Kidney Margin 0.0 Normal Ovary 0.8(OD04338) Kidney Ca Nuclear grade 0.2 Ovarian Cancer 1.1 1/2 (OD04339)064008 Kidney Margin 1.1 Ovarian Cancer 0.7 (OD04339) (OD04768-07)Kidney Ca, Clear cell 0.3 Ovary Margin 2.9 type (OD04340) (OD04768-08)Kidney Margin 1.8 Normal Stomach 15.1 (OD04340) Kidney Ca, Nuclear grade3 0.0 Gastric Cancer 6.4 (OD04348) 9060358 Kidney Margin 1.3 StomachMargin 2.0 (OD04348) 9060359 Kidney Cancer 0.0 Gastric Cancer 8.8(OD04622-01) 9060395 Kidney Margin 0.0 Stomach Margin 8.4 (OD04622-03)9060394 Kidney Cancer 0.1 Gastric Cancer 0.9 (OD04450-01) 9060397 KidneyMargin 1.2 Stomach Margin 3.1 (OD04450-03) 9060396 Kidney Cancer 81206070.1 Gastric Cancer 5.3 064005

[0884] TABLE HD Panel 3D Rel. Exp. (%) Rel. Exp. (%) Ag2840, Run Ag2840,Run Tissue Name 170190088 Tissue Name 170190088 Daoy-Medulloblastoma22.1 Ca Ski-Cervical epidermoid 7.6 carcinoma (metastasis)TE671-Medulloblastoma 10.1 ES-2-Ovarian clear cell 0.0 carcinoma D283Med- 2.3 Ramos-Stimulated with 0.0 Medulloblastoma PMA/ionomycin 6 hPFSK-1-Primitive 6.2 Ramos-Stimulated with 0.0 NeuroectodermalPMA/ionomycin 14 h XF-498-CNS 8.4 MEG-01-Chronic 0.0 myelogenousleukemia (megokaryoblast) SNB-78-Glioma 5.0 Raji-Burkitt's lymphoma 0.0SF-268-Glioblastoma 1.4 Daudi-Burkitt's lymphoma 0.0 T98G-Glioblastoma0.0 U266-B-cell plasmacytoma 10.4 SK-N-SH- 2.7 CA46-Burkitt's lymphoma0.0 Neuroblastoma (metastasis) SF-295-Glioblastoma 2.9 RL-non-Hodgkin'sB-cell 5.9 lymphoma Cerebellum 3.4 JM1-pre-B-cell lymphoma 7.8Cerebellum 38.2 Jurkat-T cell leukemia 2.7 NCI-H292- 0.0TF-1-Erythroleukemia 5.0 Mucoepidermoid lung carcinoma DMS-114-Smallcell 0.0 HUT 78-T-cell lymphoma 0.0 lung cancer DMS-79-Small cell lung100.0 U937-Histiocytic lymphoma 11.0 cancer NCI-H146-Small cell 0.0KU-812-Myelogenous 31.0 lung cancer leukemia NCI-H526-Small cell 9.6769-P-Clear cell renal 6.1 lung cancer carcinoma NCI-N417-Small cell 0.0Caki-2-Clear cell renal 3.0 lung cancer carcinoma NCI-H82-Small cell 3.3SW 839-Clear cell renal 0.0 lung cancer carcinoma NCI-H157-Squamous 0.0G401-Wilms' tumor 3.7 cell lung cancer (metastasis) NCI-H1155-Large cell20.6 Hs766T-Pancreatic 9.8 lung cancer carcinoma (LN metastasis)NCI-H1299-Large cell 9.2 CAPAN-1-Pancreatic 0.0 lung canceradenocarcinoma (liver metastasis) NCI-H727-Lung 0.0 SU86.86-Pancreatic5.0 carcinoid carcinoma (liver metastasis) NCI-UMC-11-Lung 0.0BxPC-3-Pancreatic 13.0 carcinoid adenocarcinoma LX-1-Small cell lung 7.9HPAC-Pancreatic 20.7 cancer adenocarcinoma Colo-205-Colon cancer 0.0 MIAPaCa-2-Pancreatic 4.2 carcinoma KM12-Colon cancer 0.0 CFPAC-1-Pancreaticductal 13.9 adenocarcinoma KM20L2-Colon cancer 2.9 PANC-1-Pancreatic69.7 epithelioid ductal carcinoma NCI-H716-Colon cancer 0.0 T24-Bladdercarcinma 0.0 (transitional cell) SW-48-Colon 0.0 5637-Bladder carcinoma0.0 adenocarcinoma SW1116-Colon 0.0 HT-1197-Bladder carcinoma 6.4adenocarcinoma LS 174T-Colon 0.0 UM-UC-3-Bladder carcinma 2.4adenocarcinoma (transitional cell) SW-948-Colon 0.0A204-Rhabdomyosarcoma 12.5 adenocarcinoma SW-480-Colon 3.8HT-1080-Fibrosarcoma 12.1 adenocarcinoma NCI-SNU-5-Gastric 2.1MG-63-Osteosarcoma 0.0 carcinoma KATO III-Gastric 12.0SK-LMS-1-Leiomyosarcoma 16.7 carcinoma (vulva) NCI-SNU-16-Gastric 5.8SJRH30-Rhabdomyosarcoma 5.7 carcinoma (met to bone marrow)NCI-SNU-1-Gastric 2.6 A431-Epidermoid carcinoma 0.0 carcinomaRF-1-Gastric 0.0 WM266-4-Melanoma 0.0 adenocarcinoma RF-48-Gastric 7.2DU 145-Prostate carcinoma 0.0 adenocarcinoma (brain metastasis)MKN-45-Gastric 96.6 MDA-MB-468-Breast 11.4 carcinoma adenocarcinomaNCI-N87-Gastric 10.0 SCC-4-Squamous cell 0.0 carcinoma carcinoma oftongue OVCAR-5-Ovarian 3.7 SCC-9-Squamous cell 0.0 carcinoma carcinomaof tongue RL95-2-Uterine 7.2 SCC-15-Squamous cell 0.0 carcinomacarcinoma of tongue HelaS3-Cervical 0.0 CAL 27-Squamous cell 0.0adenocarcinoma carcinoma of tongue

[0885] TABLE HE Panel 4.1D Rel. Exp. (%) Rel. Exp. (%) Ag2840, RunAg2840, Run Tissue Name 204964146 Tissue Name 204964146 Secondary Th1act 6.4 HUVEC IL-1beta 0.9 Secondary Th2 act 2.0 HUVEC IFN gamma 4.0Secondary Tr1 act 4.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest4.4 HUVEC TNF alpha + IL4 5.4 Secondary Th2 rest 13.9 HUVEC IL-11 3.8Secondary Tr1 rest 8.2 Lung Microvascular EC 8.4 none Primary Th1 act3.0 Lung Microvascular EC 4.0 TNF alpha + IL-1beta Primary Th2 act 9.6Microvascular Dermal EC 4.5 none Primary Tr1 act 1.6 MicrosvasularDermal EC 0.0 TNF alpha + IL-1beta Primary Th1 rest 3.2 Bronchialepithelium 10.4 TNF alpha + IL1beta Primary Th2 rest 5.6 Small airwayepithelium 5.9 none Primary Tr1 rest 6.4 Small airway epithelium 8.5 TNFalpha + IL-1beta CD45RA CD4 6.0 Coronery artery SMC rest 0.0 lymphocyteact CD45RO CD4 6.2 Coronery artery SMC 1.0 lymphocyte act TNF alpha +IL-1beta CD8 lymphocyte act 6.4 Astrocytes rest 0.0 Secondary CD8 2.4Astrocytes TNF alpha + 1.4 lymphocyte rest IL-1beta Secondary CD8 0.0KU-812 (Basophil) rest 8.4 lymphocyte act CD4 lymphocyte none 12.5KU-812 (Basophil) 6.1 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 11.3 CCD1106(Keratinocytes) 6.7 CD95 CH11 none LAK cells rest 7.6 CCD1106(Keratinocytes) 1.8 TNF alpha + IL-1beta LAK cells IL-2 4.2 Livercirrhosis 63.3 LAK cells IL-2+IL-12 1.9 NCI-H292 none 0.0 LAK cellsIL-2+IFN 2.7 NCI-H292 IL-4 0.0 gamma LAK cells IL-2+ IL-18 6.6 NCI-H292IL-9 0.0 LAK cells 0.0 NCI-H292 IL-13 0.0 PMA/ionomycin NK Cells IL-2rest 3.4 NCI-H292 IFN gamma 0.0 Two Way MLR 3 day 6.7 HPAEC none 0.0 TwoWay MLR 5 day 5.8 HPAEC TNF alpha + IL- 3.3 1beta Two Way MLR 7 day 8.5Lung fibroblast none 29.5 PBMC rest 9.3 Lung fibroblast TNF alpha + 8.2IL-1beta PBMC PWM 1.0 Lung fibroblast IL-4 7.9 PBMC PHA-L 3.2 Lungfibroblast IL-9 10.3 Ramos (B cell) none 1.9 Lung fibroblast IL-13 4.2Ramos (B cell) 3.0 Lung fibroblast IFN 9.1 ionomycin gamma B lymphocytesPWM 1.0 Dermal fibroblast 2.3 CCD1070 rest B lymphocytes CD40L 9.4Dermal fibroblast 9.2 and IL-4 CCD1070 TNF alpha EOL-1 dbcAMP 0.8 Dermalfibroblast 4.9 CCD1070 IL-1beta EOL-1 dbcAMP 6.0 Dermal fibroblast IFN1.0 PMA/ionomycin gamma Dendritic cells none 0.9 Dermal fibroblast IL-48.1 Dendritic cells LPS 0.0 Dermal Fibroblasts rest 4.2 Dendritic cellsanti- 3.1 Neutrophils TNFa+LPS 25.0 CD40 Monocytes rest 13.8 Neutrophilsrest 66.9 Monocytes LPS 4.9 Colon 100.0 Macrophages rest 2.1 Lung 3.8Macrophages LPS 0.9 Thymus 24.5 HUVEC none 6.3 Kidney 32.1 HUVEC starved7.9

[0886] TABLE HF Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2840, Run Ag2840,Run Tissue Name 159843516 Tissue Name 159843516 Secondary Th1 act 2.0HUVEC IL-1beta 0.2 Secondary Th2 act 1.8 HUVEC IFN gamma 0.9 SecondaryTr1 act 0.5 HUVEC TNF alpha + IFN 0.3 gamma Secondary Th1 rest 1.4 HUVECTNF alpha + IL4 0.0 Secondary Th2 rest 1.3 HUVEC IL-11 0.0 Secondary Tr1rest 1.3 Lung Microvascular EC 1.0 none Primary Th1 act 0.5 LungMicrovascular EC 0.4 TNF alpha + IL-1beta Primary Th2 act 1.1Microvascular Dermal EC 0.4 none Primary Tr1 act 1.0 MicrosvasularDermal EC 0.0 TNF alpha + IL-1beta Primary Th1 rest 2.9 Bronchialepithelium 0.2 TNF alpha + IL1beta Primary Th2 rest 1.1 Small airwayepithelium 1.5 none Primary Tr1 rest 1.4 Small airway epithelium 9.2 TNFalpha + IL-1beta CD45RA CD4 0.5 Coronery artery SMC rest 0.3 lymphocyteact CD45RO CD4 0.7 Coronery artery SMC 0.0 lymphocyte act TNF alpha +IL-1beta CD8 lymphocyte act 0.3 Astrocytes rest 0.3 Secondary CD8 0.6Astrocytes TNF alpha + 0.0 lymphocyte rest IL-1beta Secondary CD8 0.2KU-812 (Basophil) rest 1.6 lymphocyte act CD4 lymphocyte none 1.5 KU-812(Basophil) 2.5 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 1.1 CCD1106(Keratinocytes) 0.6 CD95 CH11 none LAK cells rest 1.3 CCD1106(Keratinocytes) 0.0 TNF alpha + IL-1beta LAK cells IL-2 2.2 Livercirrhosis 9.6 LAK cells IL-2+IL-12 1.0 Lupus kidney 1.9 LAK cellsIL-2+IFN 1.0 NCI-H292 none 0.0 gamma LAK cells IL-2+ IL-18 0.7 NCI-H292IL-4 0.0 LAK cells 0.3 NCI-H292 IL-9 0.0 PMA/ionomycin NK Cells IL-2rest 1.1 NCI-H292 IL-13 0.0 Two Way MLR 3 day 1.0 NCI-H292 IFN gamma 0.0Two Way MLR 5 day 0.4 HPAEC none 0.1 Two Way MLR 7 day 0.2 HPAEC TNFalpha + IL- 0.6 1beta PBMC rest 1.3 Lung fibroblast none 5.0 PBMC PWM1.2 Lung fibroblast TNF alpha + 0.8 IL-1beta PBMC PHA-L 1.2 Lungfibroblast IL-4 1.8 Ramos (B cell) none 0.2 Lung fibroblast IL-9 1.8Ramos (B cell) 1.7 Lung fibroblast IL-13 1.2 ionomycin B lymphocytes PWM1.6 Lung fibroblast IFN 2.0 gamma B lymphocytes CD40L 3.2 Dermalfibroblast 1.1 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.1 Dermal fibroblast1.7 CCD1070 TNF alpha EOL-1 dbcAMP 1.0 Dermal fibroblast 0.7PMA/ionomycin CCD1070 IL-1beta Dendritic cells none 0.0 Dermalfibroblast IFN 0.7 gamma Dendritic cells LPS 0.2 Dermal fibroblast IL-40.2 Dendritic cells anti- 0.8 IBD Colitis 2 2.0 CD40 Monocytes rest 2.3IBD Crohn's 8.9 Monocytes LPS 1.2 Colon 100.0 Macrophages rest 1.3 Lung4.4 Macrophages LPS 0.0 Thymus 16.8 HUVEC none 0.0 Kidney 14.2 HUVECstarved 1.8

[0887] TABLE HG Panel 5D Rel. Exp. (%) Rel. Exp. (%) Ag2840, Run Ag2840,Run Tissue Name 169270970 Tissue Name 169270970 97457_Patient- 63.394709_Donor 2 AM - A_adipose 24.1 02go_adipose 97476_Patient- 15.894710_Donor 2 AM - B_adipose 7.9 07sk_skeletal muscle 97477_Patient- 8.894711_Donor 2 AM - C_adipose 4.5 07ut_uterus 97478_Patient- 0.094712_Donor 2 AD - A_adipose 18.3 07pl_placenta 97481_Patient- 15.794713_Donor 2 AD - B_adipose 24.1 08sk_skeletal muscle 97482_Patient 8.494714_Donor 2 AD - C_adipose 23.5 08ut_uterus 97483_Patient- 0.094742_Donor 3 U - 0.0 08pl_placenta A_Mesenchymal Stem Cells97486_Patient- 1.4 94743_Donor 3 U - 0.0 09sk_skeletal muscleB_Mesenchymal Stem Cells 97487_Patient- 5.5 94730_Donor 3 AM - A_adipose0.0 09ut_uterus 97488_Patient- 0.0 94731_Donor 3 AM - B_adipose 0.009pl_placenta 97492_Patient- 4.6 94732_Donor 3 AM - C_adipose 0.110ut_uterus 97493_Patient- 0.3 94733_Donor 3 AD - A_adipose 0.010pl_placenta 97495_Patient- 0.0 94734_Donor 3 AD - B_adipose 0.011go_adipose 97496_Patient- 0.0 94735_Donor 3 AD - C_adipose 0.011sk_skeletal muscle 97497_Patient- 0.0 77138_Liver HepG2untreated 1.111ut_uterus 97498_Patient- 0.0 73556_Heart_Cardiac stromal 0.011pl_placenta cells (primary) 97500_Patient- 48.0 81735_Small Intestine16.8 12go_adipose 97501_Patient- 100.0 72409_Kidney_Proximal 0.012sk_skeletal muscle Convoluted Tubule 97502_Patient- 18.7 82685_Smallintestine_Duodenum 0.7 12ut_uterus 97503_Patient- 0.090650_Adrenal_Adrenocortical 0.1 12pl_placenta adenoma 94721_Donor 2 U -0.0 72410_Kidney_HRCE 0.0 A_Mesenchymal Stem Cells 94722_Donor 2 U - 0.272411_Kidney_HRE 0.0 B_Mesenchymal Stem Cells 94723_Donor 2 U - 0.073139_Uterus_Uterine smooth 0.2 C_Mesenchymal Stem muscle cells Cells

[0888] Panel 1.3D Summary: Ag2840 Highest expression of the CG55906-01gene is seen in fetal and adult skeletal muscle (CTs=26-28). This geneencodes a putative adipose cell membrane-associated protein that may beupregulated during adipocyte differentiation. Due to its homology withadipophilins, it is possible that this gene product may be involved inlipid uptake. Inhibiting the action of this gene product with anantibody may therefore potentially reduce white adipose mass by limitinglipid uptake and thereby inhibiting adipose expansion. The expression inskeletal muscle may indicate that this gene product can also take uplipids in skeletal muscle. Since excess lipid storage in muscle isassociated with insulin resistance, antibody inhibition of this geneproduct could also be a treatment for the prevention ofobesity-associated insulin resistance.

[0889] Furthermore, this gene product is also moderately expressed in avariety of metabolic tissues, including pancreas, adrenal, thyroid,pituitary, adult and fetal heart, and adult and fetal liver. Thus, thisgene product may also be an antibody target for the treatment ofmetabolic disease, including Types 1 and 2 diabetes, and obesity.

[0890] Overall, this gene is expressed at moderate levels in normaltissues but at significantly lower levels in cancer cell lines on thispanel. Thus, this gene product may have a role in homeostasis of normaltissue but not in cancer cell lines.

[0891] In addition, moderate but significant expression in the cerebralcortex suggests that the protein encoded by this gene plays a role inlipid processing in the brain. LDLR has been implicated in thedevelopment of Alzheimer's disease. Therefore, inhibitors of this geneproduct may have utility in influencing the development of Alzheimer'sdisease.

[0892] Panel 2D Summary: Ag2840 The CG55906-01 gene is moderatelyexpressed in all tissue samples in panel 2. There is increasedexpression in normal kidney, colon and bladder samples when compared tothe corresponding adjacent tumor tissue. This preferential expression innormal tissues is also seen in Panel 1.3D. Thus, expression of this genecould be used to differentiate between normal and cancerous tissues.Furthermore, therapeutic modulation of the expression of this gene mightbe of use in the treatment of kidney, colon and bladder cancer.

[0893] Panel 3D Summary: Ag2840 The CG55906-01 gene is expressed at alow level in the cancer cell lines on this panel. Significant expressionis seen in lung cancer, pancreatic cancer and a leukemia cell line.Thus, the expression of this gene could be used to distinguish samplesfrom these cell lines from other samples on this panel. Furthermore,therapeutic modulation of the expression of this gene might be of use intreating the cancers that are used in the derivation of these celllines.

[0894] Panel 4.1D Summary: Ag2840 The CG55906-01 transcript is expressedin colon and in resting neutrophils (CTs=31-33). The colon expression isconsistent with panels 4D, 2.2 and 1.3. Thus, the transcript or theprotein it encodes could be used to detect colon tissue and neutrophils.

[0895] Panel 4D Summary: Ag2840 The CG55906-01 transcript is expressedin colon and in resting neutrophils. Colon expression is consistent inpanel 4D, 2.2 and 1.3. The colon expression is consistent with panels4D, 2.2 and 1.3. Thus, the transcript or the protein it encodes could beused to detect colon tissue and neutrophils. In addition, the level ofexpression of this gene is reduced in colon tissue from patients withcolitis or Crohn's disease. This suggests that designing therapeuticswith the protein encoded for by this transcript could be important forthe treatment of IBD.

[0896] Panel 5D Summary: Ag2840 The CG55906-01 gene is moderatelyexpressed in clinical specimens of adipose, skeletal muscle and uterus.This confirms expression of this gene in tissues with metabolicfunction. See Panel 1.3D for discussion of utility of this gene inmetabolic disease.

[0897] I. CG55778-01 (NOV16a) and CG55778-05 (NOV16e): Aldose Reductase

[0898] Expression of gene CG55778-01 and variant CG55778-05 was assessedusing the primer-probe set Ag2599, described in Table IA. Results of theRTQ-PCR runs are shown in Tables IB, IC, and ID. TABLE IA Probe NameAg2599 Primers Sequences Start Position SEQ ID NO Forward5′-gacctgatagacaaccctgtga-3′ 667 299 ProbeTET-5′-acggcaagtctcctgctcagattttg-3′ 710 300 Reverse5′-atcacattcctctggatttgaa-3′ 743 301

[0899] TABLE IB CNS_neurodegeneration_v1.0 Rel. Exp. Rel. Exp. (%) (%)Ag2599, Ag2599, Run Run Tissue Name 208779985 Tissue Name 208779985 AD 1Hippo 4.3 Control (Path) 3 9.1 Temporal Ctx AD 2 Hippo 13.5 Control(Path) 4 35.8 Temporal Ctx AD 3 Hippo 8.7 AD 1 Occipital Ctx 7.0 AD 4Hippo 6.8 AD 2 Occipital Ctx 0.0 (Missing) AD 5 hippo 97.3 AD 3Occipital Ctx 13.9 AD 6 Hippo 27.4 AD 4 Occipital Ctx 16.7 Control 2Hippo 8.7 AD 5 Occipital Ctx 28.7 Control 4 Hippo 10.8 AD 6 OccipitalCtx 22.7 Control (Path) 3 6.6 Control 1 Occipital 10.7 Hippo Ctx AD 1Temporal Ctx 6.4 Control 2 Occipital 19.8 Ctx AD 2 Temporal Ctx 13.1Control 3 Occipital 17.4 Ctx AD 3 Temporal Ctx 12.5 Control 4 Occipital6.3 Ctx AD 4 Temporal Ctx 23.8 Control (Path) 1 57.8 Occipital Ctx AD 5Inf Temporal 100.0 Control (Path) 2 4.2 Ctx Occipital Ctx AD 5SupTemporal 51.4 Control (Path) 3 3.5 Ctx Occipital Ctx AD 6 InfTemporal 43.8 Control (Path) 4 11.8 Ctx Occipital Ctx AD 6 Sup Temporal36.1 Control 1 Parietal 13.4 Ctx Ctx Control 1 Temporal 17.6 Control 2Parietal 50.3 Ctx Ctx Control 2 Temporal 21.9 Control 3 Parietal 19.3Ctx Ctx Control 3 Temporal 17.8 Control (Path) 1 73.2 Ctx Parietal CtxControl 4 Temporal 11.3 Control (Path) 2 12.6 Ctx Parietal Ctx Control(Path) 1 39.2 Control (Path) 3 5.7 Temporal Ctx Parietal Ctx Control(Path) 2 18.7 Control (Path) 4 49.7 Temporal Ctx Parietal Ctx

[0900] TABLE IC Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2599, Run Ag2599, Run Ag2599, Run Ag2599, Run TissueName 162292708 165645365 Tissue Name 162292708 165645365 Liver 27.5 48.6Kidney (fetal) 0.9 0.0 adenocarcinoma Pancreas 0.1 0.0 Renal ca. 786-00.0 0.0 Pancreatic ca. 0.3 2.4 Renal ca. 5.3 20.6 CAPAN 2 A498 Adrenalgland 0.9 1.6 Renal ca. RXF 0.0 1.6 393 Thyroid 1.9 2.0 Renal ca. 2.60.0 ACHN Salivary gland 0.4 2.5 Renal ca. UO- 0.0 0.0 31 Pituitary gland1.3 0.0 Renal ca. TK- 0.0 0.0 10 Brain (fetal) 0.7 6.3 Liver 0.4 0.0Brain (whole) 0.5 5.6 Liver (fetal) 0.3 3.7 Brain (amygdala) 0.3 11.3Liver ca. 0.0 0.0 (hepatoblast) HepG2 Brain (cerebellum) 0.7 3.4 Lung1.6 3.1 Brain 2.0 11.3 Lung (fetal) 0.8 2.9 (hippocampus) Brain(substantia 0.1 4.3 Lung ca. 12.7 64.2 nigra) (small cell) LX-1 Brain(thalamus) 0.4 5.3 Lung ca. 7.6 27.4 (small cell) NCI-H69 CerebralCortex 83.5 66.4 Lung ca. 4.8 11.7 (s.cell var.) SHP-77 Spinal cord 1.20.0 Lung ca. (large 0.0 0.0 cell)NCI-H460 glio/astro U87-MG 0.5 0.0 Lungca. (non- 14.1 37.4 sm. cell) A549 glio/astro U-118- 0.0 0.0 Lung ca.(non- 1.0 0.0 MG s.cell) NCI- H23 astrocytoma 5.2 3.0 Lung ca. (non- 4.522.2 SW1783 s.cell) HOP-62 neuro*; met SK-N- 0.6 1.7 Lung ca. (non- 20.939.2 AS s.cl) NCI- H522 astrocytoma SF- 0.0 0.0 Lung ca. 1.0 5.9 539(squam.) SW 900 astrocytoma SNB- 0.0 8.8 Lung ca. 1.3 5.4 75 (squam.)NCI- H596 glioma SNB-19 0.0 0.0 Mammary 4.2 5.6 gland glioma U251 0.00.0 Breast ca.* 16.4 36.1 (pl.ef) MCF-7 glioma SF-295 0.0 0.0 Breastca.* 3.3 34.4 (pl.ef) MDA- MB-231 Heart (fetal) 100.0 97.3 Breast ca.*4.1 2.2 (pl.ef) T47D Heart 1.8 10.7 Breast ca. BT- 1.0 17.1 549 Skeletalmuscle 95.3 28.3 Breast ca. 0.0 0.0 (fetal) MDA-N Skeletal muscle 1.922.1 Ovary 29.5 23.0 Bone marrow 0.0 8.4 Ovarian ca. 0.8 1.8 OVCAR-3Thymus 2.5 0.0 Ovarian ca. 1.0 8.2 OVCAR-4 Spleen 1.1 1.7 Ovarian ca.6.0 13.5 OVCAR-5 Lymph node 0.0 12.2 Ovarian ca 1.9 16.4 OVCAR-8Colorectal 10.6 4.8 Ovarian ca. 0.0 0.0 IGROV-1 Stomach 0.4 11.3 Ovarianca.* 0.5 0.0 (ascites) SK- OV-3 Small intestine 0.7 6.3 Uterus 1.5 22.5Colon ca. SW480 3.3 18.7 Placenta 0.7 3.4 Colon ca.* 4.2 4.8 Prostate0.8 1.7 SW620(SW480 met) Colon ca. HT29 1.2 3.1 Prostate ca.* 0.0 0.5(bone met)PC-3 Colon ca. HCT- 1.4 1.3 Testis 35.4 100.0 116 Colon ca.CaCo-2 42.9 23.5 Melanoma 5.0 2.0 Hs688(A).T Colon ca. 10.6 21.5Melanoma* 2.1 11.7 tissue(ODO3866) (met) Hs688(B).T Colon ca. HCC- 3.217.9 Melanoma 10.3 47.0 2998 UACC-62 Gastric ca.* (liver 0.0 0.0Melanoma 5.6 48.6 met) NCI-N87 M14 Bladder 6.0 2.3 Melanoma 3.0 1.1 LOXIMVI Trachea 0.8 4.2 Melanoma* 2.0 3.2 (met) SK- MEL-5 Kidney 0.6 0.0Adipose 4.7 12.3

[0901] TABLE ID Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2599, Run Ag2599,Run Tissue Name 161921329 Tissue Name 161921329 Normal Colon 21.3 KidneyMargin 16.2 8120608 CC Well to Mod Diff 8.4 Kidney Cancer 3.6 (ODO3866)8120613 CC Margin (ODO3866) 6.2 Kidney Margin 9.1 8120614 CC Gr.2rectosigmoid 6.3 Kidney Cancer 6.1 (ODO3868) 9010320 CC Margin (ODO3868)4.7 Kidney Margin 21.8 9010321 CC Mod Diff (ODO3920) 8.4 Normal Uterus6.3 CC Margin (ODO3920) 7.9 Uterus Cancer 064011 24.5 CC Gr.2 ascendcolon 48.6 Normal Thyroid 1.3 (ODO3921) CC Margin (ODO3921) 8.1 ThyroidCancer 0.3 064010 CC from Partial 28.7 Thyroid Cancer 1.7 Hepatectomy(ODO4309) A302152 Mets Liver Margin (ODO4309) 6.0 Thyroid Margin 15.9A302153 Colon mets to lung 2.8 Normal Breast 18.4 (OD04451-01) LungMargin (OD04451-02) 5.1 Breast Cancer 3.0 (OD04566) Normal Prostate6546-1 0.0 Breast Cancer 14.5 (OD04590-01) Prostate Cancer 3.1 BreastCancer Mets 21.2 (OD04410) (OD04590-03) Prostate Margin 9.2 BreastCancer 1.9 (OD04410) Metastasis (OD04655-05) Prostate Cancer 11.2 BreastCancer 064006 7.7 (OD04720-01) Prostate Margin 16.6 Breast Cancer 102446.7 (OD04720-02) Normal Lung 061010 22.5 Breast Cancer 5.8 9100266 LungMet to Muscle 54.0 Breast Margin 5.3 (ODO4286) 9100265 Muscle Margin24.7 Breast Cancer 35.4 (ODO4286) A209073 Lung Malignant Cancer 20.7Breast Margin 13.8 (OD03126) A2090734 Lung Margin (OD03126) 12.4 NormalLiver 1.3 Lung Cancer (OD04404) 18.2 Liver Cancer 064003 0.6 Lung Margin(OD04404) 7.9 Liver Cancer 1025 1.5 Lung Cancer (OD04565) 6.8 LiverCancer 1026 4.1 Lung Margin (OD04565) 5.7 Liver Cancer 6004-T 3.1 LungCancer (OD04237- 0.5 Liver Tissue 6004-N 1.4 01) Lung Margin (OD04237-7.4 Liver Cancer 6005-T 3.6 02) Ocular Mel Met to Liver 7.5 Liver Tissue6005-N 0.6 (ODO4310) Liver Margin (ODO4310) 6.6 Normal Bladder 5.3Melanoma Mets to Lung 0.0 Bladder Cancer 1023 13.0 (OD04321) Lung Margin(OD04321) 12.2 Bladder Cancer 6.8 A302173 Normal Kidney 18.4 BladderCancer 2.1 (OD04718-01) Kidney Ca, Nuclear grade 11.3 Bladder Normal24.5 2 (OD04338) Adjacent (OD04718- 03) Kidney Margin 13.7 Normal Ovary12.4 (OD04338) Kidney Ca Nuclear grade 1.6 Ovarian Cancer 100.0 1/2(OD04339) 064008 Kidney Margin 8.0 Ovarian Cancer 96.6 (OD04339)(OD04768-07) Kidney Ca, Clear cell 5.5 Ovary Margin 11.5 type (OD04340)(OD04768-08) Kidney Margin 8.5 Normal Stomach 10.2 (OD04340) Kidney Ca,Nuclear grade 1.0 Gastric Cancer 3.4 3 (OD04348) 9060358 Kidney Margin4.6 Stomach Margin 7.0 (OD04348) 9060359 Kidney Cancer 3.2 GastricCancer 5.1 (OD04622-01) 9060395 Kidney Margin 3.4 Stomach Margin 6.2(OD04622-03) 9060394 Kidney Cancer 1.4 Gastric Cancer 3.6 (OD04450-01)9060397 Kidney Margin 8.4 Stomach Margin 2.5 (OD04450-03) 9060396 KidneyCancer 8120607 3.7 Gastric Cancer 7.4 064005

[0902] CNS_neurodegeneration_v1.0 Summary: Ag2599 This panel confirmsexpression of the CG55778-01 gene in the central nervous system. Pleasesee Panel 1.3D for discussion of utility of this gene in the centralnervous system.

[0903] Panel 1.3D Summary: Ag2599 The CG55778-01 gene is most highlyexpressed (CT values=29-34) in the fetal heart and the testis(CT=29-31)in two runs with the same probe and primer set. This geneproduct appears to be differentially expressed in fetal (CTvalues=29-31) vs adult heart (CT values=34-35), and may be useful forthe differentiation of the adult from the fetal phenotype in thistissue. Furthermore, the higher levels of expression in fetal heartsuggest that this gene product may be involved in the development andhomeostasis of this organ. Therapeutic modulation of the expression orfunction of this gene may be useful in the treatment of diseases thataffect the heart, including cardiomyopathy, atherosclerosis,hypertension, and congenital heart defects.

[0904] This gene is also expressed in other metabolic tissues, includingadult and fetal skeletal muscle and adipose.

[0905] Aldose reductase inhibitors prevent peripheral nerve dysfunctionand morphological abnormalities in diabetic animal models. Therefore,this gene product may be a small molecule drug target for the preventionof morbidity associated with Types 1 and 2 diabetes in humans.

[0906] There also appears to be clusters of expression of this gene inliver adenocarcinoima, melanoma and lung cancer cell lines. This dataindicate that the expression of this gene might be associated with theseforms of cancer and thus, therapeutic modulation of this gene might beof use in the treatment of these cancer.

[0907] Because aldose reductase inhibitors prevent nerve degeneration inthe periphery, the cerebral cortex-preferential expression of this geneproduct in the adult suggests that inhibitors of the protein encoded bythis gene may have utility in treating neurodegenerative diseasesinvolving the cerebral cortex, such as Alzheimer's disease, Huntington'sdisease, depression and possibly even schizophrenia. Furthermore,vascular permiability is a known pathological feature of Alzheimer'sdisease. Because aldose reductase inhibitors prevent increased vascularpermiability associated with disease, inhibitors of this gene productmay also have utility in treating Alzheimer's disease by specificallyaddressing associated vascular pathology in the cerebral cortex.

[0908] Panel 2D Summary: Ag2599 The CG55778-01 gene is expressed at ahigher level in ovarian and breast cancers compared to normal adjacenttissue (CTs=27-29). There also appears to be higher expression in normalthyroid and kidney tissues compared to the adjacent tumors. Thus, theexpression of this gene could be used to distinguish malignant ovary,breast, thyroid and kidney tissue from normal tissue in these organs. Inaddition, therapeutic modulation of this gene might be of use in thetreatment of ovarian and breast cancer.

[0909] J. CG55904-01: SQUALENE DESATURASE (NOV8)

[0910] Expression of gene CG55904-01 was assessed using the primer-probeset Ag2834, described in Table JA. TABLE JA Probe Name Ag2834 SEQPrimers Sequences Start Position ID NO Forward5′-ggtaggtactgtcggtgaattg-3′ 380 302 ProbeTET-5′-cttcatcaaatgaaaataatttcgagcaag-3′- 418 303 TAMRA Reverse5′-gcaatcgcagcttcttcag-3′ 448 304

[0911] CNS_neurodegeneration_v1.0 Summary: Ag2834 Expression of theCG55904-01-gene is low/undetectable in all samples in this panel(CTs>35).

[0912] Panel 1.3D Summary: Ag2834 Expression of the CG55904-01 gene islow/undetectable in all samples in this panel (CTs>35).

[0913] Panel 2D Summary: Ag2834 Expression of the CG55904-01 gene islow/undetectable in all samples in this panel (CTS>35).

[0914] Panel 3D Summary: Ag2834 Expression of the CG55904-01 gene islow/undetectable in all samples in this panel (CTs>35).

[0915] Panel 4D Summary: Ag2834 Expression of the CG55904-01 gene islow/undetectable in all samples in this panel (CTs>35).

[0916] K. CG55920-01 (NOV12a) and CG55920-04 (NOV12b): KILON PROTEINPRECURSOR

[0917] Expression of gene CG55920-01 and variant CG55920-04 was assessedusing the primer-probe sets Ag2847 and Ag2880, described in Tables KAand KB. Results of the RTQ-PCR runs are shown in Tables KC, KD, KE, KFand KG. TABLE KA Probe Name Ag2847 Primers Sequences Start Position SEQID NO Forward 5′-agggactacagcctccagatac-3′ 388 305 ProbeTET-5′-atggcccatacacgtgttctgttcag-3′-TAMRA 431 306 Reverse5′-cattgttctgggtgtatgttga-3′ 459 307

[0918] TABLE KB Probe Name Ag2880 Primers Sequences Start Position SEQID NO Forward 5′-gctggtaccttgtgttgacact-3′ 1088 308 ProbeTET-5′-ccagcatattctacctgaagaatgcca-3′-TAMRA 1121 309 Reverse5′-aaagccttttatgggtctttga-3′ 1161 310

[0919] TABLE KC CNS_neurodegeneration_v1.0 Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Rel. Exp. (%) Tissue Ag2847, Run Ag2880, Run TissueAg2847, Run Ag2880, Run Name 208699894 209058910 Name 208699894209058910 AD 1 Hippo 5.6 2.4 Control 1.9 0.3 (Path) 3 Temporal Ctx AD 2Hippo 13.9 10.5 Control 29.3 12.8 (Path) 4 Temporal Ctx AD 3 Hippo 2.71.1 AD 1 11.0 4.6 Occipital Ctx AD 4 Hippo 3.1 0.5 AD 2 0.0 0.0Occipital Ctx (Missing) AD 5 Hippo 84.1 100.0 AD 3 1.9 1.0 Occipital CtxAD 6 Hippo 19.9 19.8 AD 4 12.2 2.7 Occipital Ctx Control 2 15.5 12.9 AD5 39.0 18.9 Hippo Occipital Ctx Control 4 2.1 1.4 AD 6 24.0 46.7 HippoOccipital Ctx Control 1.3 0.4 Control 1 0.7 0.3 (Path) 3 Occipital HippoCtx AD 1 4.6 2.0 Control 2 50.3 66.4 Temporal Occipital Ctx Ctx AD 222.8 13.9 Control 3 12.6 3.9 Temporal Occipital Ctx Ctx AD 3 2.1 0.7Control 4 1.6 1.0 Temporal Occipital Ctx Ctx AD 4 15.0 4.0 Control 69.393.3 Temporal (Path) 1 Ctx Occipital Ctx AD 5 Inf 100.0 81.8 Control 9.83.6 Temporal (Path) 2 Ctx Occipital Ctx AD 5 Sup 20.3 16.6 Control 0.60.3 Temporal (Path) 3 Ctx Occipital Ctx AD 6 Inf 24.3 28.7 Control 11.24.7 Temporal (Path) 4 Ctx Occipital Ctx AD 6 Sup 24.5 29.3 Control 1 2.50.6 Temporal Parietal Ctx Ctx Control 1 1.6 0.4 Control 2 19.3 13.3Temporal Parietal Ctx Ctx Control 2 30.1 35.6 Control 3 12.6 4.9Temporal Parietal Ctx Ctx Control 3 7.3 2.6 Control 62.9 92.7 Temporal(Path) 1 Ctx Parietal Ctx Control 3 2.6 1.3 Control 15.5 9.5 Temporal(Path) 2 Ctx Parietal Ctx Control 44.1 54.7 Control 1.2 0.3 (Path) 1(Path) 3 Temporal Parietal Ctx Ctx Control 22.7 15.7 Control 40.1 27.0(Path) 2 (Path) 4 Temporal Parietal Ctx Ctx

[0920] TABLE KD Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2847, Run Ag2880, Run Ag2847, Run Ag2880, Run TissueName 161930455 159996472 Tissue Name 161930455 159996472 Liver 1.2 0.3Kidney (fetal) 0.9 1.3 adenocarcinoma Pancreas 0.5 0.5 Renal ca. 786-00.2 0.3 Pancreatic ca. 0.0 0.0 Renal ca. 0.5 0.5 CAPAN 2 A498 Adrenalgland 1.1 1.8 Renal ca. RXF 0.0 0.0 393 Thyroid 1.4 1.4 Renal ca. 0.50.3 ACHN Salivary gland 0.3 0.3 Renal ca. UO- 4.3 4.1 31 Pituitary gland2.6 6.0 Renal ca. TK- 0.0 0.1 10 Brain (fetal) 4.8 8.7 Liver 0.0 0.1Brain (whole) 19.8 21.5 Liver (fetal) 0.1 0.1 Brain (amygdala) 20.9 31.9Liver ca. 0.0 0.0 (hepatoblast) HepG2 Brain (cerebellum) 25.0 15.2 Lung2.2 4.2 Brain 38.4 100.0 Lung (fetal) 1.2 0.4 (hippocampus) Brain(substantia 3.6 4.0 Lung ca. 0.0 0.0 nigra) (small cell) LX-1 Brain(thalamus) 5.9 9.2 Lung ca. 0.3 0.6 (small cell) NCI-H69 Cerebral Cortex100.0 40.3 Lung ca. 1.6 1.3 (s.cell var.) SHP-77 Spinal cord 11.1 2.7Lung ca. (large 0.2 0.1 cell) NCI-H460 glio/astro U87-MG 1.3 0.3 Lungca. (non- 0.0 0.0 sm. cell) A549 glio/astro U-118- 9.7 20.7 Lung ca.(non- 0.1 0.0 MG s.cell) NCI- H23 astrocytoma 2.9 1.5 Lung ca. (non- 2.01.3 SW1783 s.cell) HOP-62 neuro*; met SK-N- 0.5 2.4 Lung ca. (non- 0.10.0 AS s.cl) NCI- H522 astrocytoma SF- 0.8 0.4 Lung ca. 0.0 0.0 539(squam.) SW 900 astrocytoma SNB- 0.2 0.1 Lung ca. 0.3 0.2 75 (squam.)NCI- H596 glioma SNB-19 0.2 0.2 Mammary 1.4 3.8 gland glioma U251 0.80.4 Breast ca.* 0.0 0.0 (pl.ef) MCF-7 glioma SF-295 0.0 0.0 Breast ca.*0.7 3.8 (pl.ef) MDA- MB-231 Heart (fetal) 5.4 1.0 Breast ca.* 0.0 0.0(pl.ef) T47D Heart 4.7 1.9 Breast ca. BT- 0.2 2.0 549 Skeletal muscle22.7 6.8 Breast ca. 0.0 0.0 (fetal) MDA-N Skeletal muscle 3.8 0.6 Ovary5.2 1.4 Bone marrow 0.3 0.6 Ovarian ca. 0.9 1.0 OVCAR-3 Thymus 8.2 1.3Ovarian ca. 0.0 0.0 OVCAR-4 Spleen 0.1 0.1 Ovarian ca. 0.0 0.0 OVCAR-5Lymph node 0.7 0.6 Ovarian ca. 1.3 1.1 OVCAR-8 Colorectal 9.0 1.7Ovarian ca. 0.0 0.0 IGROV-1 Stomach 2.2 4.0 Ovarian ca.* 0.0 0.3(ascites) SK- OV-3 Small intestine 5.6 7.1 Uterus 2.2 2.5 Colon ca.SW480 0.0 0.0 Placenta 0.5 0.6 Colon ca.* 0.0 0.0 Prostate 0.7 0.3 SW620(SW480 met) Colon ca. HT29 0.0 0.0 Prostate ca.* 1.4 1.7 (bone met) PC-3Colon ca. HCT- 0.0 0.0 Testis 1.7 1.2 116 Colon ca. CaCo-2 0.0 0.0Melanoma 5.4 2.4 Hs688(A).T Colon ca. 2.5 0.9 Melanoma* 5.5 2.3tissue(ODO3866) (met) Hs688(B).T Colon ca. HCC- 0.0 0.0 Melanoma 0.0 0.02998 UACC-62 Gastric ca.* (liver 0.0 0.4 Melanoma 0.0 0.4 met) NCI-N87M14 Bladder 3.3 0.3 Melanoma 0.0 0.1 LOX IMVI Trachea 3.9 4.0 Melanoma*0.1 0.0 (met) SK- MEL-5 Kidney 2.3 0.4 Adipose 8.6 3.2

[0921] TABLE KE Panel 2D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel.Exp. (%) Ag2847, Run Ag2880, Run Ag2847, Run Ag2880, Run Tissue Name161930456 159996526 Tissue Name 161930456 159996526 Normal Colon 100.0100.0 Kidney 7.2 2.3 Margin 8120608 CC Well to Mod 2.4 4.2 Kidney Cancer0.0 0.0 Diff (ODO3866) 8120613 CC Margin 19.1 26.6 Kidney 10.7 3.0(ODO3866) Margin 8120614 CC Gr.2 2.7 3.4 Kidney Cancer 1.3 0.7rectosigmoid 9010320 (ODO3868) CC Margin 15.4 17.2 Kidney 9.6 5.1(ODO3868) Margin 9010321 CC Mod Diff 1.6 0.7 Normal Uterus 17.9 12.9(ODO3920) CC Margin 29.5 23.0 Uterus Cancer 43.2 22.7 (ODO3920) 064011CC Gr.2 ascend 17.6 17.9 Normal 7.4 12.6 colon Thyroid (ODO3921) CCMargin 18.2 22.4 Thyroid 2.0 1.0 (ODO3921) Cancer 064010 CC from Partial0.3 1.0 Thyroid 1.2 1.8 Hepatectomy Cancer (ODO4309) A302152 Mets LiverMargin 0.1 1.1 Thyroid 16.0 17.6 (ODO4309) Margin A302153 Colon mets to2.0 0.8 Normal Breast 16.7 13.2 lung (OD04451- 01) Lung Margin 3.8 4.3Breast Cancer 22.5 11.2 (OD04451-02) (OD04566) Normal Prostate 1.8 3.9Breast Cancer 9.2 8.9 6546-1 (OD04590-01) Prostate Cancer 14.3 19.3Breast Cancer 26.4 20.6 (OD04410) Mets (OD04590-03) Prostate Margin 19.916.7 Breast Cancer 2.9 4.6 (OD04410) Metastasis (OD04655-05) ProstateCancer 17.2 17.4 Breast Cancer 5.3 8.4 (OD04720-01) 064006 ProstateMargin 22.2 29.1 Breast Cancer 8.5 6.7 (OD04720-02) 1024 Normal Lung35.4 43.2 Breast Cancer 7.9 8.7 061010 9100266 Lung Met to 14.2 13.0Breast Margin 7.9 5.6 Muscle 9100265 (ODO4286) Muscle Margin 17.9 12.8Breast Cancer 10.9 13.7 (ODO4286) A209073 Lung Malignant 6.6 7.5 BreastMargin 2.5 4.1 Cancer A2090734 (OD03126) Lung Margin 10.3 10.2 NormalLiver 0.7 0.7 (OD03126) Lung Cancer 2.6 3.4 Liver Cancer 0.1 0.2(OD04404) 064003 Lung Margin 12.9 12.2 Liver Cancer 0.3 0.1 (OD04404)1025 Lung Cancer 0.9 2.0 Liver Cancer 0.2 0.1 (OD04565) 1026 Lung Margin4.0 2.1 Liver Cancer 0.1 0.1 (OD04565) 6004-T Lung Cancer 2.7 3.7 LiverTissue 0.2 0.3 (OD04237-01) 6004-N Lung Margin 17.6 16.8 Liver Cancer0.5 0.2 (OD04237-02) 6005-T Ocular Mel Met 0.1 0.3 Liver Tissue 0.1 0.0to Liver 6005-N (ODO4310) Liver Margin 0.2 0.0 Normal 10.1 17.1(ODO4310) Bladder Melanoma Mets 7.8 7.2 Bladder 1.8 1.3 to Lung Cancer1023 (OD04321) Lung Margin 31.0 23.5 Bladder 3.9 5.4 (OD04321) CancerA302173 Normal Kidney 41.8 58.2 Bladder 4.4 2.2 Cancer (OD04718-01)Kidney Ca, 3.4 7.9 Bladder 97.9 88.3 Nuclear grade 2 Normal (OD04338)Adjacent (OD04718-03) Kidney Margin 22.4 14.3 Normal Ovary 7.2 4.0(OD04338) Kidney Ca 0.7 3.5 Ovarian 14.0 14.8 Nuclear grade Cancer 1/2(OD04339) 064008 Kidney Margin 17.3 15.3 Ovarian 0.1 0.4 (OD04339)Cancer (OD04768-07) Kidney Ca, Clear 1.3 4.0 Ovary Margin 6.4 7.6 celltype (OD04768-08) (OD04340) Kidney Margin 35.4 40.1 Normal 40.6 46.3(OD04340) Stomach Kidney Ca, 0.6 0.2 Gastric Cancer 10.8 9.0 Nucleargrade 3 9060358 (OD04348) Kidney Margin 10.0 11.2 Stomach 9.8 11.3(OD04348) Margin 9060359 Kidney Cancer 2.0 0.9 Gastric Cancer 26.6 36.1(OD04622-01) 9060395 Kidney Margin 2.4 3.1 Stomach 14.2 14.7(OD04622-03) Margin 9060394 Kidney Cancer 0.0 2.1 Gastric Cancer 7.5 7.9(OD04450-01) 9060397 Kidney Margin 19.8 13.0 Stomach 5.1 3.8(OD04450-03) Margin 9060396 Kidney Cancer 2.0 1.5 Gastric Cancer 21.022.4 8120607 064005

[0922] TABLE KF Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2880, Run Ag2880,Run Tissue Name 159996551 Tissue Name 159996551 Secondary Th1 act 0.2HUVEC IL-1beta 16.0 Secondary Th2 act 0.0 HUVEC IFN gamma 17.8 SecondaryTr1 act 0.0 HUVEC TNF alpha + IFN 13.9 gamma Secondary Th1 rest 0.0HUVEC TNF alpha + IL4 15.8 Secondary Th2 rest 0.0 HUVEC IL-11 5.3Secondary Tr1 rest 0.0 Lung Microvascular EC 6.6 none Primary Th1 act0.0 Lung Microvascular EC 12.1 TNFalpha + IL-1beta Primary Th2 act 0.6Microvascular Dermal EC 4.6 none Primary Tr1 act 1.2 MicrosvasularDermal EC 1.3 TNFalpha + IL-1beta Primary Th1 rest 0.6 Bronchialepithelium 2.7 TNFalpha + IL1beta Primary Th2 rest 0.4 Small airwayepithelium 0.7 none Primary Tr1 rest 0.0 Small airway epithelium 1.6TNFalpha + IL-1beta CD45RA CD4 21.5 Coronery artery SMC rest 53.2lymphocyte act CD45RO CD4 0.7 Coronery artery SMC 27.5 lymphocyte actTNFalpha + IL-1beta CD8 lymphocyte act 0.2 Astrocytes rest 5.7 SecondaryCD8 0.5 Astrocytes TNFalpha + 5.8 lymphocyte rest IL-1beta Secondary CD80.0 KU-812 (Basophil) rest 0.7 lymphocyte act CD4 lymphocyte none 0.0KU-812 (Basophil) 0.5 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106(Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 0.0 CCD1106(Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.3 Livercirrhosis 1.3 LAK cells IL-2 + IL-12 0.2 Lupus kidney 3.5 LAK cellsIL-2 + IFN 0.2 NCI-H292 none 2.4 gamma LAK cells IL-2 + IL-18 0.2NCI-H292 IL-4 7.5 LAK cells 0.0 NCI-H292 IL-9 9.3 PMA/ionomycin NK CellsIL-2 rest 0.0 NCI-H292 IL-13 3.5 Two Way MLR 3 day 0.7 NCI-H292 IFNgamma 2.4 Two Way MLR 5 day 0.4 HPAEC none 16.5 Two Way MLR 7 day 0.1HPAEC TNF alpha + IL-1 17.4 beta PBMC rest 0.0 Lung fibroblast none 7.3PBMC PWM 0.1 Lung fibroblast TNF alpha + 3.2 IL-1 beta PBMC PHA-L 0.0Lung fibroblast IL-4 14.6 Ramos (B cell) none 7.0 Lung fibroblast IL-915.3 Ramos (B cell) 100.0 Lung fibroblast IL-13 8.4 ionomycin Blymphocytes PWM 0.4 Lung fibroblast IFN 15.2 gamma B lymphocytes CD40L0.8 Dermal fibroblast 89.5 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermalfibroblast 88.3 CCD1070 TNF alpha EOL-1 dbcAMP 0.2 Dermal fibroblast51.4 PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 0.0 Dermalfibroblast IFN 20.7 gamma Dendritic cells LPS 0.1 Dermal fibroblast IL-435.6 Dendritic cells anti- 0.6 IBD Colitis 2 5.0 CD40 Monocytes rest 1.7IBD Crohn's 6.1 Monocytes LPS 0.0 Colon 42.0 Macrophages rest 0.0 Lung16.5 Macrophages LPS 0.0 Thymus 44.4 HUVEC none 33.7 Kidney 19.2 HUVECstarved 70.7

[0923] TABLE KG Panel CNS_1 Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2847, Run Ag2880, Run Ag2847, Run Ag2880, Run TissueName 171669934 171688447 Tissue Name 171669934 171688447 BA4 Control31.2 13.0 BA17 PSP 34.2 8.7 BA4 Control2 61.6 58.6 BA17 PSP2 9.6 2.6 BA46.1 0.7 Sub Nigra 12.2 5.3 Alzheimer's2 Control BA4 36.6 15.9 Sub Nigra19.6 19.6 Parkinson's Control2 BA4 68.8 60.3 Sub Nigra 5.9 1.2Parkinson's2 Alzheimer's2 BA4 31.6 30.1 Sub Nigra 24.0 17.7 Huntington'sParkinson's2 BA4 4.6 0.0 Sub Nigra 31.9 14.6 Huntington's2 Huntington'sBA4 PSP 7.7 1.1 Sub Nigra 11.2 7.3 Huntington's2 BA4 PSP2 27.7 9.7 SubNigra 6.0 2.5 PSP2 BA4 14.5 6.3 Sub Nigra 2.5 3.2 Depression DepressionBA4 8.3 0.0 Sub Nigra 3.7 1.2 Depression2 Depression2 BA7 Control 53.223.3 Glob Palladus 5.1 2.6 Control BA7 Control2 33.7 25.3 Glob Palladus6.1 2.5 Control2 BA7 11.6 2.3 Glob Palladus 4.5 2.1 Alzheimer's2Alzheimer's BA7 16.6 5.3 Glob Palladus 1.7 1.1 Parkinson's Alzheimer's2BA7 51.4 45.1 Glob Palladus 36.6 25.5 Parkinson's2 Parkinson's BA7 42.322.8 Glob Palladus 5.3 1.2 Huntington's Parkinson's2 BA7 50.7 14.0 GlobPalladus 1.7 0.6 Huntington's2 PSP BA7 PSP 43.8 21.8 Glob Palladus 3.90.0 PSP2 BA7 PSP2 36.3 19.5 Glob Palladus 2.0 0.4 Depression BA7 12.71.2 Temp Pole 17.1 9.3 Depression Control BA9 Control 25.0 9.7 Temp Pole69.7 57.8 Control2 BA9 Control2 100.0 100.0 Temp Pole 7.9 0.3Alzheimer's BA9 8.1 1.1 Temp Pole 5.3 1.3 Alzheimer's Alzheimer's2 BA918.3 3.5 Temp Pole 30.6 13.6 Alzheimer's2 Parkinson's BA9 37.1 13.5 TempPole 29.3 11.3 Parkinson's Parkinson's2 BA9 63.3 55.1 Temp Pole 43.218.3 Parkinson's2 Huntington's BA9 55.1 32.3 Temp Pole PSP 7.0 0.5Huntington's BA9 12.2 0.9 Temp Pole 8.6 0.5 Huntington's2 PSP2 BA9 PSP15.2 4.3 Temp Pole 4.5 0.7 Depression2 BA9 PSP2 7.2 2.5 Cing Gyr 73.240.6 Control BA9 3.5 3.1 Cing Gyr 38.2 17.4 Depression Control2 BA9 7.91.6 Cing Gyr 25.5 8.8 Depression2 Alzheimer's BA17 Control 59.0 19.6Cing Gyr 9.5 1.4 Alzheimer's2 BA17 67.8 39.5 Cing Gyr 24.3 9.3 Control2Parkinson's BA17 16.8 1.8 Cing Gyr 34.4 32.8 Alzheimer's2 Parkinson's2BA17 37.4 9.1 Cing Gyr 63.7 38.4 Parkinson's Huntington's BA17 56.6 36.6Cing Gyr 12.5 4.6 Parkinson's2 Huntington's2 BA17 37.1 16.3 Cing Gyr PSP15.5 7.5 Huntington's BA17 15.9 5.1 Cing Gyr PSP2 5.8 0.0 Huntington's2BA17 6.1 0.0 Cing Gyr 2.9 0.0 Depression Depression BA17 28.1 7.1 CingGyr 9.2 1.8 Depression2 Depression2

[0924] CNS_neurodegeneration_v1.0 Summary: Ag2847/2880 No clearrelationship between the expression levels of the CG55920-01 gene andAlzheimer's disease is evident in panel CNS_neurodegeneration_v1.0. SeePanel 1.3D for discussion of utility of this gene in the central nervoussystem.

[0925] Panel 1.3D Summary: Ag2847/2880 Two experiments with twodifferent probe and primer sets show highest expression of theCG55920-01 gene, a kilon homolog, in the brain. This expression profileis consistant with published reports of kilon expression. The sequenceof kilon shows a high degree of homology to that of the chicken proteinneurotractin, a molecule involved in neurite outgrowth capable ofinteracting with LAMP.

[0926] Because this class of molecule is thought to play a role in theguidance of growing axons, and kilon is expressed specifically inneurons, it has been suggested that they confer the ability to rearrangedendritic connectivity on magnocellular neurons. Degeneration ofdendritic orphology and connectivity is a pathological characteristic ofneurodegenerative diseases, such as Alzheimer's disease. Recombinantneurotractin promotes neurite outgrowth of telencephalic neurons andinteracts with the IgSF members CEPU-1. Therefore, this gene product maybe used as a protein therapeutic to counter neurodegeneration in a rangeof neurodegenerative diseases.

[0927] In addition to the brain preferential expression on this panel,expression is relatively absent in brain cancer derived cell lines.Thus, the expression of this gene could be used to distinguishbrain-derived tissue from other tissues in the panel. Moreover,therapeutic modulation of this gene, through the use of small moleculedrugs, antibodies or protein therapeutics might be of use in thetreatment of brain cancer.

[0928] This gene is also moderately expressed in a variety of metabolictissues including pancreas, adrenal, thyroid, pituitary, adult and fetalheart, and adipose. Thus, this gene may be an antibody target for thetreatment of disease in these tissues, including Types 1 and 2 diabetes,and obesity.

[0929] Panel 2D Summary: Ag2847/2880 Two experiments with differentprobe and primer sets produce results that are in very good agreement,with highest expression of the CG55920-01 gene in a sample derived fromnormal colon tissue (CTs=27-29). In addition, there is substantialexpression of this gene in samples derived from normal colon tissue whencompared to their adjacent malignant counterparts. The trend towarddifferential expression in normal tissues over their malignantcounterparts is also seen in kidney samples and bladder samples. Thus,the expression of this gene could be used to distinguish normal colon,bladder or kidney from their malignant counterparts. Moreover,therapeutic modulation of this gene, through the use of small moleculedrugs, antibodies or protein therapeutics might be of use in thetreatment of colon, bladder or kidney cancer.

[0930] Panel 4D Summary: Ag2880 The CG55920-01 transcript is expressedin endothelial cells, fibroblasts, activated Ramos B cells and activatedCD45RA (naive) T cells but not in primary B cells. This transcriptencodes a putative adhesion molecule that has been hypothesized to beinvolved in the establishment and remodeling of neural circuits. Therole of this protein in the immune system has not been examined,however, based on its CNS function it may be involved in cell-cellbinding that leads to leukocyte interactions with endothelium resultingin leukocyte extravasastion. Alternatively, the protein encoded for bythis transcript may be important in other cellular interactions.Therapeutics designed with the protein encoded for by this transcriptcould be important in the treatment of inflammation resulting fromasthma, chronic obstructive pulmonary disease, inflammatory boweldisease, arthritis, and psoriasis. Please note that data from a secondexperiment using the probe and primer set Ag2847 is not included becausethe amp plot suggests that there were experimental difficulties withthis run.

[0931] Panel CNS_(—)1 Summary: Ag2847/2880 Two experiments withdifferent probe and primer sets produce results that are in very goodagreement, confirming expression of the CG55920-01 gene in the brain.See Panel 1.3D for discussion of utility of this gene in the centralnervous system.

[0932] L. CG55988-01: ORGANIC CATION TRANSPORTER (NOV13a)

[0933] Expression of gene CG55988-01 was assessed using the primer-probeset Ag2861, described in Table LA. Results of the RTQ-PCR runs are shownin Tables LB, LC and LD. TABLE LA Probe Name Ag2861 Primers SequencesStart Position SEQ ID NO Forward 5′-tctcttgcagattccagagagt-3′ 193 311Probe TET-5′-tgtgccttccagaacatctcttgtgg-3′-TAMRA 228 312 Reverse5′-tgaacacagaagccaagtagtg-3′ 258 313 TABLE LB Panel 1.3D Rel. Exp. (%)Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Ag2861, Run Ag2861, RunAg2861, Run Ag2861, Run Tissue Name 161974432 165721638 Tissue Name161974432 165721638 Liver 0.0 0.0 Kidney (fetal) 4.1 2.2 adenocarcinomaPancreas 0.0 0.0 Renal ca. 786-0 0.0 0.0 Pancreatic ca. 0.0 0.0 Renalca. 0.0 0.0 CAPAN2 A498 Adrenal gland 0.0 0.0 Renal ca. RXF 0.0 0.0 393Thyroid 0.0 0.0 Renal ca. 0.0 0.0 ACHN Salivary gland 0.0 0.0 Renal ca.UO- 0.0 0.0 31 Pituitary gland 0.0 0.0 Renal ca. TK- 0.0 0.0 10 Brain(fetal) 0.0 1.5 Liver 0.0 0.0 Brain (whole) 0.0 0.0 Liver (fetal) 32.335.8 Brain (amygdala) 0.0 0.0 Liver ca. 1.5 1.6 (hepatoblast) HepG2Brain (cerebellum) 0.0 0.0 Lung 0.0 0.0 Brain 0.0 1.5 Lung (fetal) 0.00.0 (hippocampus) Brain (substantia 0.0 0.0 Lung ca. 0.0 0.0 nigra)(small cell) LX-1 Brain (thalamus) 0.0 0.0 Lung ca. 0.0 0.0 (small cell)NCI-H69 Cerebral Cortex 0.5 0.0 Lung ca. 0.0 0.0 (s.cell var.) SHP-77Spinal cord 0.0 0.0 Lung ca. (large 0.0 0.0 cell) NCI-H460 glio/astroU87-MG 0.0 0.0 Lung ca. (non- 0.0 0.0 sm. cell) A549 glio/astro U-118-0.0 0.0 Lung ca. (non- 0.0 1.9 MG s.cell) NCI- H23 astrocytoma 0.0 0.0Lung ca. (non- 0.0 0.0 SW1783 s.cell) HOP-62 neuro*; met SK-N- 0.0 0.0Lung ca. (non- 0.0 0.0 AS s.cl) NCI- H522 astrocytoma SF- 0.0 0.0 Lungca. 0.0 0.0 539 (squam.) SW 900 astrocytoma SNB- 0.0 0.0 Lung ca. 1.72.0 75 (squam.) NCI- H596 glioma SNB-19 0.0 0.0 Mammary 12.8 1.6 glandglioma U251 1.1 0.0 Breast ca.* 0.0 0.0 (pl.ef) MCF-7 glioma SF-295 0.00.0 Breast ca.* 0.0 0.0 (pl.ef) MDA- MB-231 Heart (fetal) 6.9 0.0 Breastca.* 0.0 0.0 (pl.ef) T47D Heart 0.0 0.0 Breast ca. BT- 0.0 1.0 549Skeletal muscle 11.4 0.0 Breast ca. 0.0 0.0 (fetal) MDA-N Skeletalmuscle 0.0 0.0 Ovary 2.0 0.0 Bone marrow 100.0 100.0 Ovarian ca. 0.0 0.0OVCAR-3 Thymus 6.3 0.7 Ovarian ca. 0.0 0.0 OVCAR-4 Spleen 0.0 0.0Ovarian ca. 0.0 0.0 OVCAR-5 Lymph node 1.4 0.0 Ovarian ca. 0.0 0.0OVCAR-8 Colorectal 0.0 1.4 Ovarian ca. 0.0 0.0 IGROV-1 Stomach 0.0 0.0Ovarian ca.* 0.0 3.2 (ascites)SK- OV-3 Small intestine 0.0 0.0 Uterus6.7 7.9 Colon ca. SW480 0.0 0.0 Placenta 0.9 1.5 Colon ca.* 0.0 0.0Prostate 0.0 0.0 SW620 (SW480 met) Colon ca. HT29 0.0 1.4 Prostate ca.*0.0 0.0 (bone met) PC-3 Colon ca. HCT- 0.0 0.0 Testis 33.4 12.5 116Colon ca. CaCo-2 0.0 0.0 Melanoma 0.0 0.0 Hs688(A).T Colon ca. 2.8 0.0Melanoma* 0.0 0.0 tissue(ODO3866) (met) Hs688(B).T Colon ca. HCC- 0.00.0 Melanoma 0.0 0.0 2998 UACC-62 Gastric ca.* (liver 0.0 0.0 Melanoma0.0 0.5 met) NCI-N87 M14 Bladder 4.0 0.0 Melanoma 0.0 0.0 LOX IMVITrachea 11.2 0.0 Melanoma* 0.0 0.0 (met) SK- MEL-5 Kidney 0.0 0.0Adipose 1.5 0.4

[0934] TABLE LC Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2861, Run Ag2861,Run Tissue Name 161974611 Tissue Name 161974611 Normal Colon 0.6 KidneyMargin 0.0 8120608 CC Well to Mod Diff 0.5 Kidney Cancer 0.0 (ODO3866)8120613 CC Margin (ODO3866) 0.3 Kidney Margin 0.0 8120614 CC Gr.2rectosigmoid 0.0 Kidney Cancer 0.6 (ODO3868) 9010320 CC Margin (ODO3868)0.0 Kidney Margin 0.3 9010321 CC Mod Diff (ODO3920) 0.1 Normal Uterus1.0 CC Margin (ODO3920) 0.0 Uterus Cancer 064011 0.2 CC Gr.2 ascendcolon 0.2 Normal Thyroid 0.0 (ODO3921) CC Margin (ODO3921) 0.3 ThyroidCancer 0.2 064010 CC from Partial 0.1 Thyroid Cancer 0.0 Hepatectomy(ODO4309) A302152 Mets Liver Margin (ODO4309) 0.3 Thyroid Margin 0.0A302153 Colon mets to lung 0.0 Normal Breast 0.0 (OD04451-01) LungMargin (OD04451-02) 0.1 Breast Cancer 0.0 (OD04566) Normal Prostate6546-1 0.0 Breast Cancer 0.0 (OD04590-01) Prostate Cancer 0.7 BreastCancer Mets 0.1 (OD04410) (OD04590-03) Prostate Margin 0.0 Breast Cancer0.4 (OD04410) Metastasis (OD04655-05) Prostate Cancer 0.2 Breast Cancer064006 0.0 (OD04720-01) Prostate Margin 0.0 Breast Cancer 1024 0.9(OD04720-02) Normal Lung 061010 0.6 Breast Cancer 0.0 9100266 Lung Metto Muscle 0.6 Breast Margin 0.7 (ODO4286) 9100265 Muscle Margin 0.5Breast Cancer 0.4 (ODO4286) A209073 Lung Malignant Cancer 0.2 BreastMargin 0.7 (OD03126) A2090734 Lung Margin (OD03126) 0.5 Normal Liver 0.0Lung Cancer (OD04404) 0.4 Liver Cancer 064003 0.0 Lung Margin (OD04404)1.3 Liver Cancer 1025 0.0 Lung Cancer (OD04565) 0.2 Liver Cancer 10260.0 Lung Margin (OD04565) 0.8 Liver Cancer 6004-T 0.3 Lung Cancer(OD04237-01) 0.2 Liver Tissue 6004-N 0.1 Lung Margin (OD04237-02) 0.7Liver Cancer 6005-T 0.0 Ocular Mel Met to Liver 0.0 Liver Tissue 6005-N0.0 (ODO4310) Liver Margin (ODO4310) 0.0 Normal Bladder 0.0 MelanomaMets to Lung 0.7 Bladder Cancer 1023 0.2 (OD04321) Lung Margin (OD04321)3.7 Bladder Cancer 1.7 A302173 Normal Kidney 0.5 Bladder Cancer 0.6(OD04718-01) Kidney Ca, Nuclear grade 2 1.1 Bladder Normal 0.0 (OD04338)Adjacent (OD04718- 03) Kidney Margin 0.9 Normal Ovary 0.0 (OD04338)Kidney Ca Nuclear grade 0.0 Ovarian Cancer 0.2 1/2 (OD04339) 064008Kidney Margin 0.0 Ovarian Cancer 100.0 (OD04339) (OD04768-07) Kidney Ca,Clear cell 0.1 Ovary Margin 0.0 type (OD04340) (OD04768-08) KidneyMargin 0.0 Normal Stomach 0.0 (OD04340) Kidney Ca, Nuclear grade 0.7Gastric Cancer 0.1 3 (OD04348) 9060358 Kidney Margin 0.0 Stomach Margin0.5 (OD04348) 9060359 Kidney Cancer 1.1 Gastric Cancer 0.0 (OD04622-01)9060395 Kidney Margin 0.0 Stomach Margin 0.6 (OD04622-03) 9060394 KidneyCancer 0.0 Gastric Cancer 0.7 (OD04450-01) 9060397 Kidney Margin 0.0Stomach Margin 0.0 (OD04450-03) 9060396 Kidney Cancer 8120607 0.3Gastric Cancer 0.2 064005

[0935] TABEL LD Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2861, Run Ag2861,Run Tissue Name 159616582 Tissue Name 159616582 Secondary Th1 act 0.0HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 SecondaryTr1 act 0.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVECTNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1rest 0.0 Lung Microvascular EC 1.4 none Primary Th1 act 0.0 LungMicrovascular EC 0.0 TNFalpha + IL-1beta Primary Th2 act 0.0Microvascular Dermal EC 0.0 none Primary Tr1 act 0.0 MicrosvasularDermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 0.0 Bronchialepithelium 0.0 TNFalpha + IL-1beta Primary Th2 rest 1.7 Small airwayepithelium 0.0 none Primary Tr1 rest 0.0 Small airway epithelium 0.0TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0lymphocyte act CD45RO CD4 0.0 Coronery artery SMC 0.0 lymphocyte actTNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 SecondaryCD8 0.6 Astrocytes TNFalpha + 0.0 lymphocyte rest IL-1beta Secondary CD80.0 KU-812 (Basophil) rest 54.3 lymphocyte act CD4 lymphocyte none 0.0KU-812 (Basophil) 71.2 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106(Keratinocytes) 2.6 CD95 CH11 none LAK cells rest 12.8 CCD1106(Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 0.0 Livercirrhosis 4.5 LAK cells IL-2 + IL-12 1.1 Lupus kidney 0.0 LAK cellsIL-2 + IFN 1.0 NCI-H292 none 0.0 gamma LAK cells IL-2 + IL-18 0.8NCI-H292 IL-4 0.0 LAK cells 0.0 NCI-H292 IL-9 0.0 PMA/ionomycin NK CellsIL-2 rest 0.0 NCI-H292 IL-13 1.4 Two Way MLR 3 day 11.0 NCI-H292 IFNgamma 0.0 Two Way MLR 5 day 0.6 HPAEC none 0.0 Two Way MLR 7 day 0.0HPAEC TNF alpha + IL-1 0.0 beta PBMC rest 3.8 Lung fibroblast none 0.0PBMC PWM 0.0 Lung fibroblast TNF alpha + 0.0 IL-1 beta PBMC PHA-L 0.0Lung fibroblast IL-4 2.5 Ramos (B cell) none 0.0 Lung fibroblast IL-90.0 Ramos (B cell) 0.0 Lung fibroblast IL-13 3.0 ionomycin B lymphocytesPWM 0.0 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 1.3 Dermalfibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 0.0 Dermal fibroblast0.0 CCD1070 TNF alpha EOL-1 dbcAMP 0.0 Dermal fibroblast 0.0PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 25.3 Dermalfibroblast IFN 0.0 gamma Dendritic cells LPS 100.0 Dermal fibroblastIL-4 0.0 Dendritic cells anti- 69.7 IBD Colitis 2 0.0 CD40 Monocytesrest 36.1 IBD Crohn's 0.0 Monocytes LPS 7.4 Colon 0.0 Macrophages rest94.0 Lung 2.1 Macrophages LPS 31.9 Thymus 0.0 HUVEC none 0.0 Kidney 34.4HUVEC starved 0.0

[0936] Panel 1.3D Summary: Ag2861 The expression of the CG55988-01 geneis highest in bone marrow (CTs=31-32) in two experiments with the sameprobe and primer. In addition, there was substantial expression insamples derived from testis and fetal liver. This expression profile isconsistant with published data (See references below). Thus, theexpression of this gene could be used to distinguish these tissues fromother tissues in the panel. Furthermore, the higher levels of expressionin fetal liver when compared to adult liver suggest that this geneproduct may be involved in the development and homeostasis of the liver.Thus, therapeutic modulation of the expression or function of theprotein encoded by this gene may be effective in the treatment ofdiseases that affect the liver or the function of this gene product inthe liver.

[0937] Panel 4D Summary: Ag2861 The CG55988-01 transcript is expressedin KU-812 cells, macrophages and dendritic cells (CTs=31-33). Thetranscript is more highly expressed in resting macrophages and monocytesthan in treated cells of these types, but is induced in anti-CD40 or LPStreated dendritic cells. The protein encoded by this transcript may beimportant in monocytic differentiation and in dendritic celldifferentiation and activation. Therefore, regulating the expression ofthis transcript or the function of the protein it encodes could alterthe types and levels of monocytic cells regualted by cytokine andchemlkine production and T cell activation. Therapeutics designed withthe protein encoded by this transcript could therefore be important forthe treatment of asthma, emhysema, inflammatory bowel disease, arthritisand psoriasis.

[0938] M. CG56001-01: 3-HYDROXYBUTYRATE DEHYDROGENASE (NOV14a)

[0939] Expression of gene CG56001-01 was assessed using the primer-probeset Ag2868. described in Table MA. Results of the RTQ-PCR runs are shownin TABLES MB, MC, MD, ME and MF. TABLE MA Probe Name Ag2868 PrimersSequences Start Position SEQ ID NO Forward 5′-ctactactggtggctgcgaat-3′1025 314 Probe TET-5′-cagatcatgacccacttgcctggag-3′-TAMRA 1047 315Reverse 5′-actcttcagcggatgtagatca-3′ 1084 316

[0940] TABLE MB CNS neurodegeneration_v1.0 Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Rel. Exp. (%) Tissue Ag2868, Run Ag2868, Run TissueAg2868, Run Ag2868, Run Name 206485413 224079571 Name 206485413224079571 AD 1 Hippo 10.7 11.1 Control 8.2 9.7 (Path) 3 Temporal Ctx AD2 Hippo 32.1 39.2 Control 50.7 56.3 (Path) 4 Temporal Ctx AD 3 Hippo 8.74.0 AD 1 16.0 20.6 Occipital Ctx Ad 4 Hippo 12.3 9.6 AD 2 0.0 0.0Occipital Ctx (Missing) AD 5 Hippo 99.3 74.2 AD 3 6.3 8.4 Occipital CtxAD 6 Hippo 34.4 35.8 AD 4 24.8 22.7 Occipital Ctx Control 2 27.9 29.3 AD5 48.3 19.3 Hippo Occipital Ctx Control 4 15.4 13.1 AD 6 18.2 43.5 HippoOccipital Ctx Control 8.7 12.9 Control 1 6.6 5.5 (Path) 3 OccipitalHippo Ctx AD 1 12.4 9.7 Control 2 67.4 60.7 Temporal Occipital Ctx CtxAD 2 34.9 40.6 Control 3 26.2 28.9 Temporal Occipital Ctx Ctx AD 3 6.35.0 Control 4 7.6 5.5 Temporal Occipital Ctx Ctx AD 4 13.4 28.9 Control92.0 68.8 Temporal (Path) 1 Ctx Occipital Ctx AD 5 Inf 100.0 100.0Control 18.9 15.6 Temporal (Path) 2 Ctx Occipital Ctx AD 5 Sup 57.0 46.3Control 3.8 2.7 Temporal (Path) 3 Ctx Occipital Ctx AD 6 Inf 32.3 33.4Control 35.1 30.6 Temporal (Path) 4 Ctx Occipital Ctx AD 6 Sup 45.4 39.0Control 1 15.5 10.1 Temporal Parietal Ctx Ctx Control 1 10.0 12.6Control 2 47.0 36.3 Temporal Parietal Ctx Ctx Control 2 53.6 43.2Control 3 17.3 29.5 Temporal Parietal Ctx Ctx Control 3 28.1 20.7Control 94.6 77.9 Temporal (Path) 1 Ctx Parietal Ctx Control 3 16.8 15.6Control 35.4 41.2 Temporal (Path) 2 Ctx Parietal Ctx Control 73.2 63.3Control 4.3 6.2 (Path) 1 (Path) 3 Temporal Parietal Ctx Ctx Control 57.843.2 Control 68.8 59.5 (Path) 2 (Path) 4 Temporal Parietal Ctx Ctx

[0941] TABLE MC Panel 1.3D Rel. Exp. (%) Ag2868, Rel. Exp. (%) Ag2868,Tissue Name Run 162011291 Tissue Name Run 162011291 Liver adenocarcinoma0.5 Kidney (fetal) 9.1 Pancreas 1.1 Renal ca. 786-0 0.0 Pancreatic ca.CAPAN 2 1.6 Renal ca. A498 1.1 Adrenal gland 1.0 Renal ca. RXF 393 2.8Thyroid 9.9 Renal ca. ACHN 1.5 Salivary gland 7.0 Renal ca. UO-31 2.7Pituitary gland 3.0 Renal ca. TK-10 3.4 Brain (fetal) 3.3 Liver 36.9Brain (whole) 23.5 Liver (fetal) 24.7 Brain (amygdala) 13.7 Liver ca.5.0 (hepatoblast) HepG2 Brain (cerebellum) 28.3 Lung 1.4 Brain(hippocampus) 31.6 Lung (fetal) 3.4 Brain (substantia nigra) 8.5 Lungca. (small cell) 2.8 LX-1 Brain (thalamus) 16.8 Lung ca. (small cell)7.1 NCI-H69 Cerebral Cortex 100.0 Lung ca. (s.cell var.) 3.1 SHP-77Spinal cord 10.2 Lung ca. (large 0.3 cell)NCI-H460 glio/astro U87-MG 1.3Lung ca. (non-sm. 0.7 cell) A549 glio/astro U-118-MG 0.4 Lung ca.(non-s.cell) 0.6 NCI-H23 astrocytoma SW1783 4.7 Lung ca. (non-s.cell)2.8 HOP-62 neuro*; met SK-N-AS 1.0 Lung ca. (non-s.cl) 0.4 NCI-H522astrocytoma SF-539 6.5 Lung ca. (squam.) 0.9 SW 900 astrocytoma SNB-751.4 Lung ca. (squam.) 3.4 NCI-H596 glioma SNB-19 11.5 Mammary gland 9.9glioma U251 5.1 Breast ca.* (pl.ef) 13.3 MCF-7 glioma SF-295 0.5 Breastca.* (pl.ef) 3.2 MDA-MB-231 Heart (fetal) 45.1 Breast ca.* (pl.ef) 12.2T47D Heart 21.9 Breast ca. BT-549 1.6 Skeletal muscle (fetal) 27.9Breast ca. MDA-N 3.9 Skeletal muscle 20.2 Ovary 10.4 Bone marrow 3.5Ovarian ca. OVCAR-3 4.5 Thymus 30.1 Ovarian ca. OVCAR-4 2.6 Spleen 3.0Ovarian ca. OVCAR-5 3.7 Lymph node 2.4 Ovarian ca. OVCAR-8 5.3Colorectal 52.5 Ovarian ca. IGROV-1 0.7 Stomach 6.7 Ovarian ca.*(ascites) 1.0 SK-OV-3 Small intestine 17.1 Uterus 1.2 Colon ca. SW4809.7 Placenta 0.2 Colon ca.* 3.8 Prostate 14.5 SW620(SW480 met) Colon ca.HT29 13.1 Prostate ca.* (bone 1.1 met)PC-3 Colon ca. HCT-116 3.5 Testis2.3 Colon ca. CaCo-2 14.1 Melanoma 0.1 Hs688(A).T Colon ca. 17.8Melanoma* (met) 0.6 tissue(ODO3866) Hs688(B).T Colon ca. HCC-2998 18.0Melanoma UACC-62 0.0 Gastric ca.* (liver met) 7.9 Melanoma M14 2.3NCI-N87 Bladder 5.6 Melanoma LOX 0.2 IMVI Trachea 28.5 Melanoma* (met)0.1 SK-MEL-5 Kidney 29.9 Adipose 1.0

[0942] TABLE MD Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2868, Run Ag2868,Run Tissue Name 162011370 Tissue Name 162011370 Normal Colon 43.8 KidneyMargin 9.7 8120608 CC Well to Mod Diff 5.9 Kidney Cancer 31.9 (ODO3866)8120613 CC Margin (ODO3866) 8.9 Kidney Margin 13.8 8120614 CC Gr.2rectosigmoid 19.1 Kidney Cancer 4.9 (ODO3868) 9010320 CC Margin(ODO3868) 1.4 Kidney Margin 17.1 9010321 CC Mod Diff (ODO3920) 34.2Normal Uterus 0.3 CC Margin (ODO3920) 15.7 Uterus Cancer 064011 3.4 CCGr.2 ascend colon 38.4 Normal Thyroid 8.0 (ODO3921) CC Margin (ODO3921)16.0 Thyroid Cancer 7.5 064010 CC from Partial 28.7 Thyroid Cancer 6.8Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 100.0 ThyroidMargin 8.2 A302153 Colon mets to lung 6.7 Normal Breast 4.6 (OD04451-01)Lung Margin (OD04451-02) 0.8 Breast Cancer 12.1 (OD04566) NormalProstate 6546-1 4.1 Breast Cancer 22.1 (OD04590-01) Prostate Cancer 20.3Breast Cancer Mets 22.7 (OD04410) (OD04590-03) Prostate Margin 16.3Breast Cancer 23.8 (OD04410) Metastasis (OD04655-05) Prostate Cancer 8.4Breast Cancer 064006 4.8 (OD04720-01) Prostate Margin 11.2 Breast Cancer1024 41.2 (OD04720-02) Normal Lung 061010 6.7 Breast Cancer 16.0 9100266Lung Met to Muscle 0.5 Breast Margin 6.9 (ODO4286) 9100265 Muscle Margin0.3 Breast Cancer 5.5 (ODO4286) A209073 Lung Malignant Cancer 10.4Breast Margin 7.8 (OD03126) A2090734 Lung Margin (OD03126) 4.1 NormalLiver 55.5 Lung Cancer (OD04404) 20.9 Liver Cancer 064003 17.7 LungMargin (OD04404) 1.4 Liver Cancer 1025 70.7 Lung Cancer (OD04565) 3.7Liver Cancer 1026 20.3 Lung Margin (OD04565) 1.3 Liver Cancer 6004-T90.1 Lung Cancer (OD04237-01) 14.2 Liver Tissue 6004-N 5.2 Lung Margin(OD04237-02) 1.0 Liver Cancer 6005-T 17.2 Ocular Mel Met to Liver 6.8Liver Tissue 6005-N 32.5 (ODO4310) Liver Margin (ODO4310) 58.6 NormalBladder 5.4 Melanoma Mets to Lung 5.7 Bladder Cancer 1023 2.8 (OD04321)Lung Margin (OD04321) 2.9 Bladder Cancer 2.5 A302173 Normal Kidney 30.1Bladder Cancer 7.2 (OD04718-01) Kidney Ca, Nuclear grade 2 42.9 BladderNormal 1.4 (OD04338) Adjacent (OD04718-03) Kidney Margin 17.6 NormalOvary 1.5 (OD04338) Kidney Ca Nuclear grade 7.3 Ovarian Cancer 9.6 1/2(OD04339) 064008 Kidney Margin 14.7 Ovarian Cancer 1.4 (OD04339)(OD04768-07) Kidney Ca, Clear cell 0.3 Ovary Margin 0.2 type (OD04340)(OD04768-08) Kidney Margin 14.1 Normal Stomach 4.8 (OD04340) Kidney Ca,Nuclear grade 3 0.2 Gastric Cancer 0.6 (OD04348) 9060358 Kidney Margin7.3 Stomach Margin 5.0 (OD04348) 9060359 Kidney Cancer 9.3 GastricCancer 7.9 (OD04622-01) 9060395 Kidney Margin 4.0 Stomach Margin 6.8(OD04622-03) 9060394 Kidney Cancer 10.7 Gastric Cancer 16.8 (OD04450-01)9060397 Kidney Margin 11.7 Stomach Margin 3.4 (OD04450-03) 9060396Kidney Cancer 8120607 2.4 Gastric Cancer 8.0 064005

[0943] TABLE ME Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2868, Run Ag2868,Run Tissue Name 159776784 Tissue Name 159776784 Secondary Th1 act 48.0HUVEC IL-1beta 0.1 Secondary Th2 act 40.9 HUVEC IFN gamma 2.7 SecondaryTr1 act 55.1 HUVEC TNF alpha + IFN 0.3 gamma Secondary Th1 rest 3.1HUVEC TNF alpha + IL4 1.1 Secondary Th2 rest 7.8 HUVEC IL-11 2.6Secondary Tr1 rest 12.5 Lung Microvascular EC 1.9 none Primary Th1 act64.6 Lung Microvascular EC 1.8 TNFalpha + IL-1beta Primary Th2 act 52.9Microvascular Dermal EC 1.0 none Primary Tr1 act 88.3 MicrosvasularDermal EC 1.4 TNFalpha + IL-1beta Primary Th1 rest 54.0 Bronchialepithelium 1.1 TNFalpha + IL1beta Primary Th2 rest 30.6 Small airwayepithelium 3.8 none Primary Tr1 rest 100.0 Small airway epithelium 14.2TNFalpha + IL-1beta CD45RA CD4 17.0 Coronery artery SMC rest 0.3lymphocyte act CD45RO CD4 33.0 Coronery artery SMC 0.0 lymphocyte actTNFalpha + IL-1beta CD8 lymphocyte act 30.8 Astrocytes rest 3.0Secondary CD8 30.8 Astrocytes TNFalpha + 1.7 lymphocyte rest IL-1betaSecondary CD8 16.4 KU-812 (Basophil) rest 25.3 lymphocyte act CD4lymphocyte none 3.5 KU-812 (Basophil) 50.0 PMA/ionomycin 2ryTh1/Th2/Tr1_anti- 9.9 CCD1106 (Keratinocytes) 12.7 CD95 CH11 none LAKcells rest 10.2 CCD1106 (Keratinocytes) 0.5 TNFalpha + IL-1beta LAKcells IL-2 24.5 Liver cirrhosis 3.8 LAK cells IL-2 + IL-12 30.4 Lupuskidney 2.0 LAK cells IL-2 + IFN 31.4 NCI-H292 none 31.4 gamma LAK cellsIL-2 + IL-18 33.0 NCI-H292 IL-4 36.1 LAK cells 1.8 NCI-H292 IL-9 41.8PMA/ionomycin NK Cells IL-2 rest 14.5 NCI-H292 IL-13 25.5 Two Way MLR 3day 6.4 NCI-H292 IFN gamma 23.7 Two Way MLR 5 day 13.6 HPAEC none 1.0Two Way MLR 7 day 11.7 HPAEC TNF alpha + IL-1 0.2 beta PBMC rest 2.0Lung fibroblast none 1.5 PBMC PWM 43.8 Lung fibroblast TNF alpha + 0.3IL-1 beta PBMC PHA-L 22.7 Lung fibroblast IL-4 1.0 Ramos (B cell) none23.7 Lung fibroblast IL-9 1.9 Ramos (B cell) 62.9 Lung fibroblast IL-130.7 ionomycin B lymphocytes PWM 76.8 Lung fibroblast IFN 0.5 gamma Blymphocytes CD40L 26.6 Dermal fibroblast 1.8 and IL-4 CCD1070 rest EOL-1dbcAMP 27.2 Dermal fibroblast 31.6 CCD1070 TNF alpha EOL-1 dbcAMP 12.3Dermal fibroblast 2.3 PMA/ionomycin CCD1070 IL-1 beta Dendritic cellsnone 8.1 Dermal fibroblast IFN 0.2 gamma Dendritic cells LPS 3.1 Dermalfibroblast IL-4 2.6 Dendritic cells anti- 5.9 IBD Colitis 2 0.6 CD40Monocytes rest 1.2 IBD Crohn's 3.0 Monocytes LPS 0.9 Colon 31.6Macrophages rest 15.1 Lung 2.9 Macrophages LPS 1.4 Thymus 29.5 HUVECnone 1.7 Kidney 11.9 HUVEC starved 1.8

[0944] TABLE MF Panel 5 Islet Rel. Exp. (%) Rel. Exp. (%) Ag2868, RunAg2868, Run Tissue Name 233071460 Tissue Name 233071460 97457_Patient-1.6 94709_Donor 2 AM - A_adipose 6.4 02go_adipose 97476_Patient- 0.094710_Donor 2 AM - B_adipose 0.0 07sk_skeletal muscle 97477_Patient- 3.594711_Donor 2 AM - C_adipose 0.0 07ut_uterus 97478_Patient- 9.494712_Donor 2 AD - A_adipose 4.0 07pl_placenta 99167_Bayer Patient 112.2 94713_Donor 2 AD - B_adipose 2.0 97482_Patient- 0.7 94714_Donor 2AD - C_adipose 0.0 08ut_uterus 97483_Patient- 4.0 94742_Donor 3 U - 0.008pl_placenta A_Mesenchymal Stem Cells 97486_Patient- 0.0 94743_Donor 3U - 0.0 09sk_skeletal muscle B_Mesenchymal Stem Cells 97487_Patient- 4.094730_Donor 3 AM - A_adipose 3.9 09ut_uterus 97488_Patient- 9.894731_Donor 3 AM - B_adipose 1.7 09pl_placenta 97492_Patient- 6.694732_Donor 3 AM - C_adipose 4.1 10ut_uterus 97493_Patient- 6.194733_Donor 3 AD - A_adipose 1.2 10pl_placenta 97495_Patient- 7.594734_Donor 3 AD - B_adipose 2.0 11go_adipose 97496_Patient- 12.594735_Donor 3 AD - C_adipose 3.7 11sk_skeletal muscle 97497_Patient- 3.977138_Liver_HepG2untreated 85.3 11ut_uterus 97498_Patient- 5.073556_Heart_Cardiac stromal 0.0 11pl_placenta cells (primary)97500_Patient- 13.8 81735_Small Intestine 58.2 12go_adipose97501_Patient- 20.6 72409_Kidney_Proximal 11.6 12sk_skeletal muscleConvoluted Tubule 97502_Patient- 1.3 82685_Small intestine_Duodenum 58.212ut_uterus 97503_Patient- 2.1 90650_Adrenal_Adrenocortical 5.412pl_placenta adenoma 94721_Donor 2 U - 2.9 72410_Kidney_HRCE 100.0A_Mesenchymal Stem Cells 94722_Donor 2 U - 1.5 72411_Kidney_HRE 35.1B_Mesenchymal Stem Cells 94723_Donor 2 U - 3.3 73139_Uterus_Uterinesmooth 0.0 C_Mesenchymal Stem muscle cells Cells

[0945] CNS_neurodegeneration_v1.0 Summary: Ag2868 No association isevident between the CG56001-01 gene expression levels and Alzheimer'sdisease. This is not surprising however, because D-beta-hydroxybutyratedehydrogenase function appears to be controlled, at the translational,post-translational and catalytic levels. (See ref. below). This panelconfirms expression of this gene in the brain. See Panel 1.3D fordiscussion of utility of this gene in the central nervous system.

[0946] Panel 1.3D Summary: Ag2868 Expression of the CG56001-01 gene ishighest in the cerebral cortex (CT=27.6). The expression of this gene inmultiple brain regions is consistent with a published role for this genein CNS energetic processes. D-beta-hydroxybutyrate protects neurons inmodels of Alzheimer's and Parkinson's disease. Other enzymes, such asamyloid beta-peptide-binding alcohol dehydrogenase, which have beenshown to possess D-beta-hydroxybutyrate dehydrogenase activity,contribute to the protective response to metabolic stress, especially inthe setting of ischemia. Since this gene prodcut processesD-beta-hydroxybutyrate to provide a neuronal energy source, activatorsof the protein encoded by this gene may be useful in treating andprotecting the CNS of Alzheimer's and Parkinson's disease patients, aswell as stroke.

[0947] Overall, expression of this gene appears to be largely associatedwith normal tissues when compared to cancer cell lines. Thus, theexpression of this gene could be used to distinguish normal tissues fromthe other tissues in the panel. Moreover, therapeutic modulation of thisgene, through the use of small molecule drugs, antibodies or proteintherapeutics might be of benefit in the treatment of cancer.

[0948] This gene is also moderately expressed in a variety of metabolictissues, including pancreas, adrenal, thyroid, pituitary, adult andfetal heart, adult and fetal skeletal muscle, adult and fetal liver andadipose. This gene encodes a hydroxybutyrate dehydrogenase homolog.Mutations in this fatty acid-oxidation enzyme are associated withhypoglycemia and cardiac arrest. Activators of this enzyme could be drugtargets for obesity because increased fatty acid oxidation may preventthe incorporation of fatty acids into triglylcerides, thus decreasingadipose mass.

[0949] Panel 2D Summary: Ag2868 The expression of the CG56001-01 geneappears to be highest in a sample derived from normal liver tissueadjacent to a metastatic colon cancer (CT=25.9). In addition, thereappears to be substantial expression associated with malignant livertissue when compared to their associated normal adjacent tissue. Thus,the expression of this gene could be used to distinguish liver derivedtissue from the other samples in the panel. Moreover, therapeuticmodulation of this gene, through the use of small molecule drugs,antibodies or protein therapeutics might be of benefit in the treatmentof liver cancer.

[0950] Panel 4D Summary: Ag2868 The CG56001-01 transcript is expressedprimarily in activated leukocytes, especially in T cells and B cells(CTs=27-30). It is also expressed in NCI-H292 cells and in TNF alphatreated dermal fibroblasts. The protein encoded by this trancript hashomology to hydroxybutyrate dehydrogenase, a protein that has been foundin lymphocytes (ref below). Thus, the protein encoded for by thistranscript may be important for cellular responses toinflammatory/activating stimuli. Therefore, therapeutics designed withthe protein encoded for by this transcript could be used for thetreatment of inflammatory diseases such as asthma, emphysema, COPD,arthritis, IBD and psoriasis.

[0951] Panel 5 Islet Summary: Ag2868 Expression of the CG56001-01 geneis highest a in kidney cell line (CT-32.8). Thus, expression of thisgene could be used to differentiate between this sample and othersamples on this panel.

[0952] N. SC145665404_A/CG55069-01 (NOV15a) and CG55069-02 (NOV15b) andCG55069-03 (NOV15c): TEN-M3 Like

[0953] Expression of gene SC145665404_A and variants CG55069-02 andCG55069-03 was assessed using the primer-probe sets Ag2674, Ag1479 andAg2820, described in Tables NA, NB and NC. Results of the RTQ-PCR runsare shown in Tables ND, NE, NF, and NG. TABLE NA Probe Name Ag2674Primers Sequences Start Position SEQ ID NO Forward5′-acctactcggccactacctaga-3′ 993 317 ProbeTET-5′-caccctatcaagaagtgcttttaaattca-3′-TAMRA 1017 318 Reverse5′-cagtgcatttccagctacagta-3′ 1060 319

[0954] TABLE NB Probe Name Ag1479 Primers Sequences Start Position SEQID NO Forward 5′-cacggaacgtatcttcaagaaa-3′ 2125 320 ProbeTET-5′-ctgcacgtgtgaccctaactggactg-3′-TAMRA 2154 321 Reverse5′-gccacagtccacagaacatatt-3′ 2199 322

[0955] TABLE NC Probe Name Ag2820 Primers Sequences Start Position SEQID NO Forward 5′-cagagaagcagacgagttcact-3′ 354 323 ProbeTET-5′-caaggacagaattttaccctaaggca-3′-TAMRA 379 324 Reverse5′-gttgctggttcacaaactccta-3′ 407 325

[0956] TABLE ND CNS_neurodegeneration_v1.0 Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Rel. Exp. (%) Ag2674, Run Ag2674, Run Tissue Ag2674, RunAg2674, Run Tissue Name 206976322 237982180 Name 206976322 237982180 AD1 Hippo 20.7 20.9 Control 12.1 10.2 (Path) 3 Temporal Ctx AD 2 Hippo31.4 30.4 Control 39.5 37.1 (Path) 4 Temporal Ctx AD 3 Hippo 18.9 9.7 AD1 11.5 11.9 Occipital Ctx AD 4 Hippo 7.9 6.8 AD 2 0.0 0.0 Occipital Ctx(Missing) AD 5 hippo 100.0 60.3 AD 3 7.9 6.0 Occipital Ctx AD 6 Hippo62.9 61.6 AD 4 15.4 17.8 Occipital Ctx Control 2 34.9 29.9 AD 5 0.0 34.4Hippo Occipital Ctx Control 4 15.6 8.3 AD 6 40.3 28.9 Hippo OccipitalCtx Control (Path) 18.3 19.3 Control 1 7.4 4.5 3 Hippo Occipital Ctx AD1 Temporal 21.2 16.2 Control 2 42.9 28.3 Ctx Occipital Ctx AD 2 Temporal39.0 38.4 Control 3 18.8 17.1 Ctx Occipital Ctx AD 3 Temporal 14.8 9.9Control 4 9.1 7.6 Ctx Occipital Ctx AD 4 Temporal 26.4 32.1 Control 72.246.7 Ctx (Path) 1 Occipital Ctx AD 5 Inf 84.7 100.0 Control 13.7 14.3Temporal Ctx (Path) 2 Occipital Ctx AD 5 35.4 59.5 Control 6.4 6.3SupTemporal (Path) 3 Ctx Occipital Ctx AD 6 Inf 64.6 54.0 Control 16.213.1 Temporal Ctx (Path) 4 Occipital Ctx AD 6 Sup 54.0 44.8 Control 112.0 8.7 Temporal Ctx Parietal Ctx Control 1 19.8 13.9 Control 2 46.349.3 Temporal Ctx Parietal Ctx Control 2 47.0 30.1 Control 3 17.7 19.2Temporal Ctx Parietal Ctx Control 3 35.4 31.4 Control 59.5 48.6 TemporalCtx (Path) 1 Parietal Ctx Control 4 16.5 16.6 Control 25.5 25.3 TemporalCtx (Path) 2 Parietal Ctx Control (Path) 63.3 50.0 Control 6.9 7.7 1Temporal Ctx (Path) 3 Parietal Ctx Control (Path) 31.6 34.2 Control 31.230.1 2 Temporal Ctx (Path) 4 Parietal Ctx

[0957] TABLE NE Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag1479, Run Ag2674, Run Ag2820, Run Ag2820, Run TissueName 165520101 162554642 165527000 165544916 Liver 16.0 15.9 17.2 8.2adenocarcinoma Pancreas 0.5 0.1 0.0 0.1 Pancreatic ca. 16.2 4.9 10.4 6.3CAPAN 2 Adrenal gland 4.1 0.8 4.9 2.7 Thyroid 2.0 0.8 0.6 0.2 Salivarygland 0.2 0.1 0.0 0.1 Pituitary gland 3.5 0.6 0.8 0.1 Brain (fetal) 8.70.6 2.3 1.1 Brain (whole) 10.4 2.0 1.7 2.1 Brain (amygdala) 12.8 3.0 2.02.0 Brain (cerebellum) 10.0 1.8 0.3 0.3 Brain (hippocampus) 17.7 5.0 3.52.1 Brain (substantia 1.8 0.0 0.4 0.1 nigra) Brain (thalamus) 19.3 2.22.2 3.2 Cerebral Cortex 8.0 100.0 4.8 3.6 Spinal cord 1.4 1.1 0.4 1.0glio/astro U87-MG 13.6 12.0 18.8 26.1 glio/astro U-118-MG 82.4 20.9100.0 100.0 astrocytoma 27.9 21.5 24.8 19.3 SW1783 neuro*; met SK-N-31.2 8.7 18.8 16.3 AS astrocytoma SF-539 25.2 19.8 22.2 19.3 astrocytomaSNB-75 20.6 5.2 27.2 15.7 glioma SNB-19 4.7 1.6 4.0 3.4 glioma U251100.0 7.9 88.3 76.8 glioma SF-295 5.6 3.3 5.6 3.5 Heart (fetal) 1.0 4.30.3 0.3 Heart 0.7 0.3 0.0 0.0 Skeletal muscle 1.0 32.8 2.3 1.3 (fetal)Skeletal muscle 6.0 2.0 0.0 0.2 Bone marrow 0.0 0.0 0.0 0.0 Thymus 0.20.7 0.5 0.6 Spleen 0.7 0.3 1.0 0.9 Lymph node 2.0 0.2 2.4 2.0 Colorectal0.3 3.2 0.5 0.1 Stomach 3.4 0.1 2.2 0.1 Small intestine 3.5 0.6 1.3 0.7Colon ca. SW480 1.6 0.7 2.4 2.0 Colon ca.* 0.0 0.0 0.0 0.0 SW620 (SW480met) Colon ca. HT29 0.7 0.7 0.6 0.8 Colon ca. HCT-116 0.3 0.0 0.0 0.1Colon ca. CaCo-2 8.6 14.3 9.7 7.4 Colon ca. 2.6 2.5 2.6 1.4tissue(ODO3866) Colon ca. HCC-2998 1.0 0.4 2.4 1.2 Gastric ca.* (liver0.9 0.3 2.4 0.6 met) NCI-N87 Bladder 0.9 2.5 2.3 0.4 Trachea 0.8 0.3 0.00.2 Kidney 0.8 0.5 0.0 0.0 Kidney (fetal) 2.8 1.4 2.5 1.3 Renal ca.786-0 11.2 6.4 19.9 9.5 Renal ca. A498 13.1 4.3 13.2 7.2 Renal ca. RXF393 21.5 7.2 21.3 26.1 Renal ca. ACHN 10.1 5.1 7.6 7.5 Renal ca. UO-3110.2 3.3 13.8 9.5 Renal ca. TK-10 0.0 0.0 0.0 0.0 Liver 0.0 0.0 0.0 0.0Liver (fetal) 0.1 0.0 0.0 0.0 Liver ca. 0.2 0.2 0.0 0.4 (hepatoblast)HepG2 Lung 0.4 0.1 0.2 0.0 Lung (fetal) 0.3 0.3 0.0 0.7 Lung ca. (smallcell) 0.0 0 0 0.0 0.0 LX-1 Lung ca. (small cell) 3.1 11.6 5.4 11.2NCI-H69 Lung ca. (s.cell var.) 2.4 1.7 0.0 0.0 SHP-77 Lung ca. (large18.6 2.6 26.1 12.9 cell) NCI-H460 Lung ca. (non-sm. 0.4 0.1 0.6 0.2cell) A549 Lung ca. (non-s.cell) 1.4 2.1 1.2 0.1 NCI-H23 Lung ca.(non-s.cell) 9.5 3.9 16.0 6.8 HOP-62 Lung ca. (non-s.cl) 28.1 36.9 15.35.8 NCI-H522 Lung ca. (squam.) 0.6 0.1 0.2 0.1 SW 900 Lung ca. (squam.)16.5 8.0 19.2 12.3 NCI-H596 Mammary gland 0.7 0.5 0.5 0.2 Breast ca.*(pl.ef) 5.0 8.8 5.1 2.1 MCF-7 Breast ca.* (pl.ef) 2.4 0.3 0.5 0.4MDA-MB-231 Breast ca.* (pl.ef) 53.6 26.1 1.9 1.1 T47D Breast ca. BT-5490.0 0.0 0.0 0.0 Breast ca. MDA-N 0.8 1.1 1.5 1.1 Ovary 0.8 2.8 0.3 0.0Ovarian ca. 58.6 19.3 26.8 20.0 OVCAR-3 Ovarian ca. 2.4 0.4 3.1 2.0OVCAR-4 Ovarian ca. 0.0 0.0 0.0 0.0 OVCAR-5 Ovarian ca. 8.7 6.7 1.7 2.8OVCAR-8 Ovarian ca. IGROV-1 3.1 1.5 0.0 0.4 Ovarian ca.* 27.9 6.7 22.20.0 (ascites) SK-OV-3 Uterus 2.4 0.4 1.2 0.9 Placenta 8.1 4.4 7.7 4.1Prostate 2.1 0.1 0.0 0.0 Prostate ca.* (bone 0.7 1.1 0.0 0.0 met)PC-3Testis 4.5 1.1 0.0 0.1 Melanoma 10.0 20.4 12.8 7.5 Hs688(A).T Melanoma*(met) 12.5 18.9 12.0 42 Hs688(B).T Melanoma UACC- 1.2 0.3 0.4 0.3 62Melanoma M14 13.7 2.1 14.4 7.8 Melanoma LOX 1.2 1.2 0.0 0.0 IMVIMelanoma* (met) 3.7 4.5 3.8 1.8 SK-MEL-5 Adipose 3.6 4.5 12.9 0.6

[0958] TABLE NF Panel 2D Rel. Rel. Rel. Rel. Rel. Rel. Exp. (%) Exp. (%)Exp. (%) Exp. (%) Exp. (%) Exp. (%) Ag2674, Ag2820, Ag2820, Ag2674,Ag2820, Ag2820, Tissue Run Run Run Tissue Run Run Run Name 162455917163578010 165910586 Name 162455917 163578010 165910586 Normal 47.6 12.415.7 Kidney 6.9 1.7 3.7 Colon Margin 8120608 CC Well to 8.4 7.2 7.4Kidney 0.5 0.0 0.0 Mod Diff Cancer (ODO3866) 8120613 CC Margin 8.0 0.80.4 Kidney 2.8 1.6 0.0 (ODO3866) Margin 8120614 CC Gr.2 5.4 3.8 2.3Kidney 22.4 39.5 36.1 rectosigmoid Cancer (ODO3868) 9010320 CC Margin12.4 2.2 1.2 Kidney 14.1 22.5 11.6 (ODO3868) Margin 9010321 CC Mod 0.40.7 0.0 Normal 7.1 4.1 7.0 Diff Uterus (ODO3920) CC Margin 12.2 1.6 1.4Uterus 38.4 5.5 2.3 (ODO3920) Cancer 064011 CC Gr.2 3.8 2.9 3.6 Normal13.9 4.7 1.1 ascend colon Thyroid (ODO3921) CC Margin 8.9 1.3 0.0Thyroid 30.4 36.3 40.9 (ODO3921) Cancer 064010 CC from 6.0 12.3 12.5Thyroid 8.3 5.8 2.8 Partial Cancer Hepatectomy A302152 (ODO4309) MetsLiver 0.4 0.4 0.0 Thyroid 88.3 10.0 7.2 Margin Margin (ODO4309) A302153Colon mets 1.4 1.5 1.1 Normal 26.4 9.5 11.3 to lung Breast (OD04451- 01)Lung Margin 0.7 0.0 0.8 Breast 2.0 0.7 0.8 (OD04451- Cancer 02)(OD04566) Normal 14.1 6.3 2.0 Breast 13.7 4.0 2.9 Prostate Cancer 6546-1(OD04590- 01) Prostate 26.8 4.9 4.1 Breast 55.1 32.5 15.9 Cancer Cancer(OD04410) Mets (OD04590- 03) Prostate 27.0 6.0 1.9 Breast 24.8 12.2 2.9Margin Cancer (OD04410) Metastasis (OD04655- 05) Prostate 18.8 3.2 1.2Breast 11.2 7.5 5.5 Cancer Cancer (OD04720- 064006 01) Prostate 41.2 8.03.9 Breast 11.1 1.8 1.3 Margin Cancer (OD04720- 1024 02) Normal 16.013.4 11.8 Breast 11.8 3.5 1.2 Lung Cancer 061010 9100266 Lung Met to25.5 64.2 39.2 Breast 13.2 4.9 1.7 Muscle Margin (ODO4286) 9100265Muscle 14.1 1.3 1.1 Breast 19.2 3.5 1.7 Margin Cancer (ODO4286) A209073Lung 44.8 66.9 57.8 Breast 25.3 0.6 2.0 Malignant Margin Cancer A2090734(OD03126) Lung Margin 11.7 10.6 5.9 Normal 1.7 1.2 0.3 (OD03126) LiverLung Cancer 13.7 10.4 11.6 Liver 0.5 0.0 0.0 (OD04404) Cancer 064003Lung Margin 11.4 10.7 14.4 Liver 0.0 0.0 0.0 (OD04404) Cancer 1025 LungCancer 13.1 8.5 4.5 Liver 0.7 0.0 0.0 (OD04565) Cancer 1026 Lung Margin3.1 5.3 6.2 Liver 0.5 0.0 0.0 (OD04565) Cancer 6004-T Lung Cancer 7.413.6 4.5 Liver 0.6 1.0 0.3 (OD04237- Tissue 01) 6004-N Lung Margin 4.85.3 3.8 Liver 1.1 0.0 0.0 (OD04237- Cancer 02) 6005-T Ocular Mel 0.9 0.00.0 Liver 0.0 0.0 0.0 Met to Liver Tissue (ODO4310) 6005-N Liver 5.0 0.00.3 Normal 26.1 14.7 12.7 Margin Bladder (ODO4310) Melanoma 29.7 57.431.6 Bladder 6.0 9.2 2.0 Mets to Cancer Lung 1023 (OD04321) Lung Margin4.3 7.0 3.5 Bladder 6.0 3.9 2.3 (OD04321) Cancer A302173 Normal 27.718.9 14.4 Bladder 41.8 89.5 82.4 Kidney Cancer (OD04718- 01) Kidney Ca,2.9 5.6 2.9 Bladder 22.4 3.5 3.9 Nuclear Normal grade 2 Adjacent(OD04338) (OD04718- 03) Kidney 11.8 10.8 9.0 Normal 10.1 2.1 0.6 MarginOvary (OD04338) Kidney Ca 48.3 82.4 67.8 Ovarian 100.0 36.3 100.0Nuclear Cancer grade 1/2 064008 (OD04339) Kidney 15.9 17.7 8.8 Ovarian0.3 0.0 0.4 Margin Cancer (OD04339) (OD04768- 07) Kidney Ca, 0.8 0.0 0.3Ovary 8.2 6.9 4.4 Clear cell Margin type (OD04768- (OD04340) 08) Kidney21.6 13.9 8.0 Normal 5.7 2.2 1.9 Margin Stomach (OD04340) Kidney Ca,33.4 84.7 58.2 Gastric 7.2 3.0 2.8 Nuclear Cancer grade 3 9060358(OD04348) Kidney 12.9 4.6 11.1 Stomach 4.9 0.7 1.5 Margin Margin(OD04348) 9060359 Kidney 1.4 0.0 4.6 Gastric 6.5 1.9 1.8 Cancer Cancer(OD04622- 9060395 01) Kidney 7.3 3.9 1.1 Stomach 7.2 2.2 2.3 MarginMargin (OD04622- 9060394 03) Kidney 84.7 100.0 78.5 Gastric 46.7 22.728.5 Cancer Cancer (OD04450- 9060397 01) Kidney 19.9 12.0 6.9 Stomach4.7 0.7 0.0 Margin Margin (OD04450- 9060396 03) Kidney 12.7 4.9 4.2Gastric 5.6 9.2 6.5 Cancer Cancer 8120607 064005

[0959] TABLE NG Panel 4D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%) Rel.Exp. (%) Ag1479, Run Ag2674, Run Ag2820, Run Ag2820, Run Tissue Name162599612 160645450 162350531 164329602 Secondary Th1 act 0.3 0.0 0.00.0 Secondary Th2 act 0.0 0.0 0.0 0.5 Secondary Tr1 act 0.0 0.0 0.0 0.3Secondary Th1 rest 0.0 0.0 0.0 0.0 Secondary Th2 rest 0.0 0.0 0.0 0.0Secondary Tr1 rest 0.0 0.0 0.0 0.0 Primary Th1 act 0.0 0.0 0.0 0.0Primary Th2 act 0.0 0.0 0.0 0.0 Primary Tr1 act 0.0 0.0 0.0 0.0 PrimaryTh1 rest 0.0 0.5 0.0 0.0 Primary Th2 rest 0.0 0.0 0.0 0.0 Primary Tr1rest 0.0 0.0 0.0 0.0 CD45RA CD4 1.8 1.0 1.6 0.8 lymphocyte act CD45ROCD4 0.0 0.0 0.0 0.0 lymphocyte act CD8 lymphocyte act 0.0 0.0 0.0 0.0Secondary CD8 0.0 0.0 0.0 0.0 lymphocyte rest Secondary CD8 0.0 0.0 0.00.0 lymphocyte act CD4 lymphocyte none 0.0 0.0 0.0 0.0 2ryTh1/Th2/Tr1_anti- 0.0 0.0 0.0 0.0 CD95 CH11 LAK cells rest 0.0 0.0 0.00.0 LAK cells IL-2 0.0 0.0 0.3 0.0 LAK cells IL-2 + IL-12 0.0 0.0 0.00.7 LAK cells IL-2 + IFN 0.0 0.0 0.0 0.0 gamma LAK cells IL-2 + IL-180.0 0.0 0.0 0.0 LAK cells 0.0 0.0 0.0 0.5 PMA/ionomycin NK Cells IL-2rest 0.0 0.0 0.0 0.0 Two Way MLR 3 day 0.0 0.0 0.0 0.0 Two Way MLR 5 day0.0 0.0 0.0 0.0 Two Way MLR 7 day 0.0 0.0 0.0 0.0 PBMC rest 0.0 0.0 0.00.0 PBMC PWM 0.0 0.0 0.0 0.0 PBMC PHA-L 0.0 0.0 0.0 0.0 Ramos (B cell)none 0.0 0.0 0.0 0.0 Ramos (B cell) 0.0 0.0 0.0 0.0 ionomycin Blymphocytes PWM 0.0 0.0 0.3 2.5 B lymphocytes CD40L 0.2 0.4 0.0 0.0 andIL-4 EOL-1 dbcAMP 0.2 0.2 0.3 0.7 EOL-1 dbcAMP 0.1 0.2 0.9 0.0PMA/ionomycin Dendritic cells none 0.0 0.0 0.0 0.0 Dendritic cells LPS0.0 0.0 0.0 0.0 Dendritic cells anti- 0.0 0.0 0.0 0.0 CD40 Monocytesrest 0.0 0.0 0.0 0.0 Monocytes LPS 0.0 0.0 0.0 0.0 Macrophages rest 0.00.0 0.0 0.0 Macrophages LPS 0.0 0.0 0.0 0.0 HUVEC none 23.0 17.7 0.0 0.0HUVEC starved 25.0 26.1 0.0 0.0 HUVEC IL-1beta 8.1 7.1 0.0 0.0 HUVEC IFNgamma 14.8 13.8 0.0 0.3 HUVEC TNF alpha + 8.1 6.7 0.0 0.0 IFN gammaHUVEC TNF alpha + 12.0 10.2 0.0 0.0 IL4 HUVEC IL-11 8.5 7.0 0.0 0.0 LungMicrovascular EC 11.1 14.2 0.0 0.0 none Lung Microvascular EC 9.3 11.00.0 0.2 TNFalpha + IL-1beta Microvascular Dermal 100.0 75.3 0.0 0.0 ECnone Microsvasular Dermal 29.7 26.8 0.0 0.0 EC TNFalpha + IL- 1betaBronchial epithelium 0.2 1.3 2.4 19.9 TNFalpha + IL1beta Small airwayepithelium 2.2 1.1 1.0 1.7 none Small airway epithelium 0.3 0.2 0.0 0.0TNFalpha + IL-1beta Coronery artery SMC 8.3 8.0 1.9 2.6 rest Coroneryartery SMC 4.6 3.1 3.0 1.2 TNFalpha + IL-1beta Astrocytes rest 85.9 70.2100.0 100.0 Astrocytes TNFalpha + 59.0 100.0 71.7 65.5 IL-1beta KU-812(Basophil) rest 0.0 0.3 0.0 0.0 KU-812 (Basophil) 0.0 0.0 0.0 0.0PMA/ionomycin CCD1106 19.8 17.2 35.6 70.2 (Keratinocytes) none CCD11061.7 1.3 13.4 29.3 (Keratinocytes) TNFalpha + IL-1beta Liver cirrhosis0.0 0.5 0.3 0.0 Lupus kidney 1.8 2.9 6.2 8.1 NCI-H292 none 0.0 0.0 0.00.0 NCI-H292 IL-4 0.0 0.0 0.3 0.4 NCI-H292 IL-9 0.0 0.0 0.0 0.0 NCI-H292IL-13 0.0 0.0 0.0 0.0 NCI-H292 IFN gamma 0.0 0.0 0.0 0.0 HPAEC none 15.112.2 0.0 0.0 HPAEC TNF alpha + 6.2 7.5 0.6 0.0 IL-1 beta Lung fibroblastnone 0.9 0.4 0.0 0.4 Lung fibroblast TNF 0.6 0.0 0.0 0.0 alpha + IL-1beta Lung fibroblast IL-4 2.1 2.9 1.7 3.7 Lung fibroblast IL-9 1.2 0.51.2 2.0 Lung fibroblast IL-13 1.2 0.9 1.6 3.3 Lung fibroblast IFN 2.11.9 2.3 0.2 gamma Dermal fibroblast 10.5 9.8 10.3 8.4 CCD1070 restDermal fibroblast 11.6 4.6 10.0 11.3 CCD1070 TNF alpha Dermal fibroblast4.9 2.2 4.5 3.8 CCD1070 IL-1 beta Dermal fibroblast IFN 1.2 1.7 0.3 1.6gamma Dermal fibroblast IL-4 28.3 27.9 12.1 13.4 IBD Colitis 2 0.7 1.60.3 0.0 IBD Crohn's 1.6 0.4 0.8 3.7 Colon 8.6 7.6 1.7 1.9 Lung 2.0 2.93.8 6.3 Thymus 7.0 13.7 4.1 4.4 Kidney 17.0 27.5 13.0 20.2

[0960] CNS neurodegeneration_v1.0 Summary: Ag2674 While no associationbetween expression of the SC145665404_A gene and Alzheimer's disease isapparent in this panel, the profile here confirms expression of thisgene in the brain. See Panel 1.3D for discussion of potential utility ofthis gene in the brain.

[0961] Panel 13D Summary: Ag1479/2674/Ag2820 The SC145665404_A geneencodes a protein that is homologous to ten-m3 and may be involved inbrain compartmentation. In multiple experiments with different probe andprimer sets highest expression of this gene is seen in the brain and inbrain cancer cell lines. Thus, inhibitors of this gene product couldhave utility in diseases involving neurite outgrowth or organization,such as neurodegenerative diseases.

[0962] In addition to expression in brain cancer cell lines, there issubstantial expression in other samples derived from cancer cell lines,such as breast cancer, lung cancer, and ovarian cancer. Thus, theexpression of this gene could be used to distinguish these samples fromother samples in the panel. Moreover, therapeutic modulation of thisgene, through the use of small molecule drugs, antibodies or proteintherapeutics might be of use in the treatment of brain cancer, lungcancer, breast cancer or ovarian cancer.

[0963] This gene is also moderately expressed metabolic tissuesincluding adrenal, thyroid, pituitary, fetal heart, adult and fetalskeletal muscle, and adipose. Thus, this gene product may be an antibodytarget for the treatment of any or all diseases in these tissues,including obesity and diabetes.

[0964] Panel 2D Summary: Ag2674/2820 The expression of the SC145665404_Agene was assessed in three independent runs in panel 2D using twodifferent probe/primer sets. The highest expression of this gene isgenerally associated with kidney cancers. Of particular note is theconsistent absence of expression in normal kidney tissue adjacent tomalignant kidney. In addition, there is substantial expressionassociated with ovarian cancer, bladder cancer and lung cancer. Thus,the expression of this gene could be used to distinguish the abovelisted malignant tissue from other tissues in the panel. Particularly,the expression of this gene could be used to distinguish malignantkidney tissue from normal kidney. Moreover, therapeutic modulation ofthis gene, through the use of small molecule drugs, antibodies orprotein therapeutics might be of benefit in the treatment of kidneycancer, ovarian cancer, bladder cancer or lung cancer.

[0965] Panel 4D Summary: Ag1479/Ag2674/Ag2820 The expression of theSC145665404_A transcript is highest in astrocytes and microvasculardermal endothelial cells (CTs=29-30), with low but significantexpression in keratinocytes, and dermal fibroblasts. Expression is notmodulated by any treatment, suggesting that this protein may beimportant in normal homeostasis. Thus, this transcript or the protein itencodes could be used to identify the tissues and cells in which it isexpressed.

[0966] O. CG55910-01: ACYL-COA DESATURASE 1 (NOV10)

[0967] Expression of gene CG55910-01 was assessed using the primer-probesets Ag2839 and Ag2031, described in Tables OA and OB. Results of theRTQ-PCR runs are shown in Tables OC, OD, OE, OF, OG and OH. TABLE OAProbe Name Ag2839 Primers Sequences Start Position SEQ ID NO Forward5′-ggcttccataattaccatcaca-3′ 1067 326 ProbeTET-5′-cctttccctttgactactctgcgagtg-3′-TAMRA 1089 327 Reverse5′-gcacatgaaatcaatgaacca-3′ 1145 328

[0968] TABLE OB Probe Name Ag2031 Primers Sequences Start Position SEQID NO Forward 5′-ggcttccataattaccatcaca-3′ 1067 329 ProbeTET-5′-cctttccctttgactactctgcgagtg-3′-TAMRA 1089 330 Reverse5′-gcacatgaaatcaatgaacca-3′ 1145 331

[0969] TABLE OC CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag2839, Rel.Exp. (%) Ag2839, Tissue Name Run 209052444 Tissue Name Run 209052444 AD1 Hippo 17.2 Control (Path) 3 7.8 Temporal Ctx AD 2 Hippo 43.5 Control(Path) 4 25.2 Temporal Ctx AD 3 Hippo 8.4 AD 1 Occipital Ctx 15.1 AD 4Hippo 11.9 AD 2 Occipital Ctx 0.0 (Missing) AD 5 hippo 54.3 AD 3Occipital Ctx 7.3 AD 6 Hippo 55.5 AD 4 Occipital Ctx 23.8 Control 2Hippo 47.0 AD 5 Occipital Ctx 18.0 Control 4 Hippo 15.7 AD 6 OccipitalCtx 49.0 Control (Path) 3 7.7 Control 1 Occipital 4.4 Hippo Ctx AD 1Temporal Ctx 16.6 Control 2 Occipital 75.8 Ctx AD 2 Temporal Ctx 44.4Control 3 Occipital 18.0 Ctx AD 3 Temporal Ctx 6.7 Control 4 Occipital12.2 Ctx AD 4 Temporal Ctx 28.1 Control (Path) 1 73.7 Occipital Ctx AD 5Inf Temporal 100.0 Control (Path) 2 9.9 Ctx Occipital Ctx AD 5SupTemporal 69.7 Control (Path) 3 3.7 Ctx Occipital Ctx AD 6 InfTemporal 44.1 Control (Path) 4 8.4 Ctx Occipital Ctx AD 6 Sup Temporal43.5 Control 1 Parietal 11.5 Ctx Ctx Control 1 Temporal 11.7 Control 2Parietal 36.1 Ctx Ctx Control 2 Temporal 53.2 Control 3 Parietal 21.6Ctx Ctx Control 3 Temporal 17.3 Control (Path) 1 64.6 Ctx Parietal CtxControl 4 Temporal 14.8 Control (Path) 2 23.8 Ctx Parietal Ctx Control(Path) 1 58.6 Control (Path) 3 6.5 Temporal Ctx Parietal Ctx Control(Path) 2 32.8 Control (Path) 4 31.4 Temporal Ctx Parietal Ctx

[0970] TABLE OD. Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2031, Run Ag2839, Run Ag2031, Run Ag2839, Run TissueName 152479705 164023720 Tissue Name 152479705 164023720 Liver 5.2 7.4Kidney (fetal) 2.0 1.6 adenocarcinoma Pancreas 5.8 2.1 Renal ca. 786-00.0 0.0 Pancreatic ca. 0.5 0.3 Renal ca. 0.4 0.7 CAPAN 2 A498 Adrenalgland 12.9 6.9 Renal ca. RXF 0.0 0.0 393 Thyroid 8.5 4.8 Renal ca. 0.70.4 ACHN Salivary gland 1.6 0.5 Renal ca. UO- 0.5 0.1 31 Pituitary gland11.5 6.4 Renal ca. TK- 0.0 0.0 10 Brain (fetal) 15.3 9.1 Liver 0.3 0.0Brain (whole) 45.7 29.7 Liver (fetal) 0.2 0.1 Brain (amygdala) 44.1 27.5Liver ca. 0.0 0.0 (hepatoblast) HepG2 Brain (cerebellum) 19.5 30.1 Lung2.7 2.3 Brain 100.0 39.2 Lung (fetal) 2.3 1.1 (hippocampus) Brain(substantia 17.8 10.3 Lung ca. 0.3 0.1 nigra) (small cell) LX-1 Brain(thalamus) 32.1 25.5 Lung ca. 0.9 0.4 (small cell) NCI-H69 CerebralCortex 89.5 100.0 Lung ca. 0.0 0.0 (s.cell var.) SHP-77 Spinal cord 39.251.1 Lung ca. (large 0.6 0.3 cell) NCI-H460 glio/astro U87-MG 1.1 2.6Lung ca. (non- 0.5 0.5 sm. cell) A549 glio/astro U-118- 1.4 0.3 Lung ca.(non- 1.8 1.1 MG s.cell) NCI- H23 astrocytoma 0.3 0.6 Lung ca. (non- 1.00.7 SW1783 s.cell) HOP-62 neuro*; met SK-N- 1.4 0.4 Lung ca. (non- 1.30.8 AS s.cl) NCI- H522 astrocytoma SF- 1.2 1.0 Lung ca. 1.5 1.1 539(squam.) SW 900 astrocytoma SNB- 2.7 0.8 Lung ca. 0.0 0.2 75 (squam.)NCI- H596 glioma SNB-19 12.6 22.2 Mammary 1.2 0.9 gland glioma U251 3.02.1 Breast ca.* 2.1 4.0 (pl.ef) MCF-7 glioma SF-295 0.6 0.4 Breast ca.*2.3 0.5 (pl.ef) MDA- MB-231 Heart (fetal) 1.6 1.2 Breast ca.* 0.0 0.0(pl.ef) T47D Heart 0.6 1.2 Breast ca. BT- 1.3 0.5 549 Skeletal muscle3.4 4.1 Breast ca. 0.0 0.0 (fetal) MDA-N Skeletal muscle 0.1 0.2 Ovary23.3 30.6 Bone marrow 0.2 0.0 Ovarian ca. 8.4 7.4 OVCAR-3 Thymus 0.7 3.6Ovarian ca. 2.3 0.9 OVCAR-4 Spleen 1.1 0.5 Ovarian ca. 1.3 1.0 OVCAR-5Lymph node 0.6 0.2 Ovarian ca. 2.1 2.0 OVCAR-8 Colorectal 0.6 0.5Ovarian ca. 0.4 0.4 IGROV-1 Stomach 2.6 0.8 Ovarian ca.* 1.4 0.8(ascites) SK- OV-3 Small intestine 2.9 1.2 Uterus 1.8 0.5 Colon ca.SW480 3.6 0.9 Placenta 0.7 0.2 Colon ca.* 0.6 0.7 Prostate 1.5 0.5 SW620(SW480 met) Colon ca. HT29 0.0 0.0 Prostate ca.* 0.6 0.5 (bone met) PC-3Colon ca. HCT- 1.5 1.6 Testis 11.0 6.7 116 Colon ca. CaCo-2 0.6 0.5Melanoma 1.2 0.3 Hs688(A).T Colon ca. 0.2 0.5 Melanoma* 0.8 0.3tissue(ODO3866) (met) Hs688(B).T Colon ca. HCC- 0.1 0.0 Melanoma 0.2 0.62998 UACC-62 Gastric ca.* (liver 4.1 2.4 Melanoma 0.2 0.2 met) NCI-N87M14 Bladder 2.0 4.5 Melanoma 0.2 0.1 LOX IMVI Trachea 2.9 2.9 Melanoma*1.4 0.5 (met) SK- MEL-5 Kidney 2.5 8.8 Adipose 0.5 0.4

[0971] TABLE OE Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2839, Ag2839,Tissue Name Run 162559077 Tissue Name Run 162559077 Normal Colon 14.1Kidney Margin 21.2 8120608 CC Well to Mod Diff 1.6 Kidney Cancer 1.1(ODO3866) 8120613 CC Margin (ODO3866) 2.2 Kidney Margin 27.7 8120614 CCGr.2 rectosigmoid 0.6 Kidney Cancer 13.6 (ODO3868) 9010320 CC Margin(ODO3868) 3.0 Kidney Margin 25.7 9010321 CC Mod Diff (ODO3920) 0.6Normal Uterus 3.0 CC Margin (ODO3920) 3.5 Uterus Cancer 064011 12.7 CCGr.2 ascend colon 3.6 Normal Thyroid 60.7 (ODO3921) CC Margin (ODO3921)2.3 Thyroid Cancer 34.4 064010 CC from Partial 3.4 Thyroid Cancer 41.2Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 0.5 ThyroidMargin 35.4 A302153 Colon mets to lung 11.0 Normal Breast 7.3(OD04451-01) Lung Margin (OD04451- 11.3 Breast Cancer 0.3 02) (OD04566)Normal Prostate 6546-1 44.4 Breast Cancer 2.6 (OD04590-01) ProstateCancer 10.0 Breast Cancer Mets 2.4 (OD04410) (OD04590-03) ProstateMargin 18.3 Breast Cancer 11.6 (OD04410) Metastasis (OD04655-05)Prostate Cancer 13.8 Breast Cancer 064006 3.9 (OD04720-01) ProstateMargin 28.1 Breast Cancer 1024 5.9 (OD04720-02) Normal Lung 061010 35.1Breast Cancer 31.4 9100266 Lung Met to Muscle 1.1 Breast Margin 12.9(ODO4286) 9100265 Muscle Margin 2.0 Breast Cancer 5.8 (ODO4286) A209073Lung Malignant Cancer 6.6 Breast Margin 4.1 (OD03126) A2090734 LungMargin (OD03126) 20.6 Normal Liver 1.0 Lung Cancer (OD04404) 15.6 LiverCancer 064003 0.1 Lung Margin (OD04404) 11.0 Liver Cancer 1025 0.5 LungCancer (OD04565) 3.1 Liver Cancer 1026 1.8 Lung Margin (OD04565) 4.6Liver Cancer 6004-T 1.1 Lung Cancer (OD04237- 20.4 Liver Tissue 6004-N0.4 01) Lung Margin (OD04237- 16.5 Liver Cancer 6005-T 0.7 02) OcularMel Met to Liver 0.6 Liver Tissue 6005-N 0.6 (ODO4310) Liver Margin(ODO4310) 0.5 Normal Bladder 42.0 Melanoma Mets to Lung 8.1 BladderCancer 1023 1.1 (OD04321) Lung Margin (OD04321) 20.9 Bladder Cancer 37.9A302173 Normal Kidney 87.7 Bladder Cancer 35.8 (OD04718-01) Kidney Ca,Nuclear grade 2 3.7 Bladder Normal 9.7 (OD04338) Adjacent (OD04718- 03)Kidney Margin 33.0 Normal Ovary 60.3 (OD04338) Kidney Ca Nuclear grade24.1 Ovarian Cancer 20.4 1/2 (OD04339) 064008 Kidney Margin 33.9 OvarianCancer 100.0 (OD04339) (OD04768-07) Kidney Ca, Clear cell 7.1 OvaryMargin 4.4 type (OD04340) (OD04768-08) Kidney Margin 52.5 Normal Stomach8.2 (OD04340) Kidney Ca, Nuclear grade 3 1.8 Gastric Cancer 4.1(OD04348) 9060358 Kidney Margin 29.1 Stomach Margin 10.0 (OD04348)9060359 Kidney Cancer 2.0 Gastric Cancer 9.3 (OD04622-01) 9060395 KidneyMargin 9.5 Stomach Margin 4.5 (OD04622-03) 9060394 Kidney Cancer 83.5Gastric Cancer 3.2 (OD04450-01) 9060397 Kidney Margin 62.9 StomachMargin 1.6 (OD04450-03) 9060396 Kidney Cancer 8120607 15.3 GastricCancer 4.8 064005

[0972] TABLE OF Panel 4D Rel. Rel. Rel. Rel. Exp. (%) Exp. (%) Exp. (%)Exp. (%) Ag2031, Ag2839, Ag2031, Ag2839, Run Run Run Run Tissue Name152784562 162294682 Tissue Name 152784562 162294682 Secondary Th1 act3.0 1.1 HUVEC IL-1beta 12.2 8.1 Secondary Th2 act 1.8 1.0 HUVEC IFN 22.721.0 gamma Secondary Tr1 act 2.1 1.2 HUVEC TNF 4.0 3.9 alpha + IFN gammaSecondary Th1 rest 0.5 0.2 HUVEC TNF 7.2 6.6 alpha + IL4 Secondary Th2rest 0.2 0.3 HUVEC IL-11 13.7 15.6 Secondary Tr1 rest 0.2 0.0 Lung 22.539.0 Microvascular EC none Primary Th1 act 1.6 1.0 Lung 10.8 9.6Microvascular EC TNF alpha + IL- 1beta Primary Th2 act 0.5 0.5Microvascular 63.7 86.5 Dermal EC none Primary Tr1 act 0.8 0.6Microvasular 17.9 19.8 Dermal EC TNF alpha + IL- 1beta Primary Th1 rest3.1 2.5 Bronchial 2.6 30.8 epithelium TNF alpha + IL1beta Primary Th2rest 0.3 0.6 Small airway 10.4 9.9 epithelium none Primary Tr1 rest 0.70.6 Small airway 100.0 100.0 epithelium TNF alpha + IL- 1beta CD45RA CD45.2 2.5 Coronery artery 14.1 18.2 lymphocyte act SMC rest CD45RO CD4 1.10.6 Coronery artery 11.7 6.9 lymphocyte act SMC TNF alpha + IL-1beta CD8lymphocyte 1.8 2.1 Astrocytes rest 77.9 79.0 act Secondary CD8 0.5 0.7Astrocytes 61.6 39.0 lymphocyte rest TNF alpha + IL- 1beta Secondary CD81.6 2.3 KU-812 0.0 0.0 lymphocyte act (Basophil) rest CD4 lymphocyte 0.10.2 KU-812 0.1 0.4 none (Basophil) PMA/ionomycin 2ry 0.3 0.5 CCD110610.8 17.4 Th1/Th2/Tr1_anti- (Keratinocytes) CD95 CH11 none LAK cellsrest 1.0 1.2 CCD1106 2.0 14.4 (Keratinocytes) TNF alpha + IL- 1beta LAKcells IL-2 5.0 6.3 Liver cirrhosis 3.1 5.0 LAK cells IL-2 + 0.8 0.9Lupus kidney 3.3 3.4 IL-12 LAK cells IL- 1.3 1.6 NCI-H292 none 40.3 53.62+IFN gamma LAK cells IL-2 + 1.0 1.6 NCI-H292 IL-4 75.3 48.0 IL-18 LAKcells 0.1 0.2 NCI-H292 IL-9 69.3 68.3 PMA/ionomycin NK Cells IL-2 rest3.5 3.8 NCI-H292 IL-13 36.3 31.0 Two Way MLR 3 1.1 1.4 NCI-H292 IFN 40.628.3 day gamma Two Way MLR 5 1.0 0.5 HPAEC none 40.9 41.5 day Two WayMLR 7 0.4 0.3 HPAEC TNF 15.6 13.5 day alpha + IL-1beta PBMC rest 0.4 0.8Lung fibroblast 5.5 4.2 none PBMC PWM 1.3 1.3 Lung fibroblast 2.6 2.2TNF alpha + IL-1 beta PBMC PHA-L 2.7 4.1 Lung fibroblast 8.6 9.8 IL-4Ramos (B cell) 2.1 1.3 Lung fibroblast 5.6 6.0 none IL-9 Ramos (B cell)5.6 11.5 Lung fibroblast 4.7 3.7 ionomycin IL-13 B lymphocytes 1.1 2.4Lung fibroblast 8.8 10.0 PWM IFN gamma B lymphocytes 0.8 0.3 Dermalfibroblast 14.8 14.0 CD40L and IL-4 CCD1070 rest EOL-1 dbcAMP 9.9 11.3Dermal fibroblast 17.6 19.2 CCD1070 TNF alpha EOL-1 dbcAMP 5.0 4.5Dermal fibroblast 5.0 3.4 PMA/ionomycin CCD1070 IL-1 beta Dendriticcells 0.2 0.1 Dermal fibroblast 9.0 5.2 none IFN gamma Dendritic cellsLPS 1.9 1.9 Dermal fibroblast 28.5 21.0 IL-4 Dendritic cells anti- 0.70.9 IBD Colitis 2 0.7 0.9 CD40 Monocytes rest 0.6 0.6 IBD Crohn's 1.41.6 Monocytes LPS 0.1 0.0 Colon 13.3 9.2 Macrophages rest 0.6 0.4 Lung18.3 14.2 Macrophages LPS 0.0 0.1 Thymus 89.5 90.1 HUVEC none 29.3 33.7Kidney 20.3 24.3 HUVEC starved 59.9 65.1

[0973] TABLE OG Panel 5D Rel. Exp. (%) Rel. Exp. (%) Ag2839, Run Ag2839,Run Tissue Name 223676497 Tissue Name 223676497 97457_Patient- 3.694709_Donor 2 AM - A_adipose 46.0 02go_adipose 97476_Patient- 3.594710_Donor 2 AM - B_adipose 22.2 07sk_skeletal muscle 97477_Patient-3.3 94711_Donor 2 AM - C_adipose 23.2 07ut_uterus 97478_Patient- 3.394712_Donor 2 AD - A_adipose 17.9 07pl_placenta 97481_Patient- 2.694713_Donor 2 AD - B_adipose 30.4 08sk_skeletal muscle 97482_Patient-2.5 94714_Donor 2 AD - C_adipose 13.9 08ut_uterus 97483_Patient- 2.794742_Donor 3 U - 3.7 08pl_placenta A_Mesenchymal Stem Cells97486_Patient- 0.8 94743_Donor 3 U - 2.7 09sk_skeletal muscleB_Mesenchymal Stem Cells 2.7 97487_Patient- 2.5 94730_Donor 3 AM -A_adipose 48.0 09ut_uterus 97488_Patient- 2.3 94731_Donor 3 AM -B_adipose 20.4 09pl_placenta 97492_Patient- 3.7 94732_Donor 3 AM -C_adipose 25.0 10ut_uterus 97493_Patient- 6.1 94733_Donor 3 AD -A_adipose 21.8 10pl_placenta 97495_Patient- 5.2 94734_Donor 3 AD -B_adipose 11.9 11go_adipose 97496_Patient- 1.3 94735_Donor AD -C_adipose 14.8 11sk_skeletal muscle 97497_Patient- 6.777138_Liver_HepG2untreated 0.7 11ut_uterus 97498_Patient- 4.273556_Heart_Cardiac stromal 39.5 11pl_placenta 97500_Patient- 9.881735_Small Intestine 13.9 12go_adipose 97501_Patient- 7.072409_Kidney_Proximal 2.0 12sk_skeletal muscle Convoluted Tubule97502_Patient- 12.3 82685_Small intestine_Duodenum 2.1 12ut_uterus97503_Patient- 4.0 90650_Adrenal_Adrenocortical 100.0 12pl_placentaadenoma 94721_Donor 2 U — 7.5 72410_Kidney_HRCE 12.7 A_Mesenchymal StemCells 94722_Donor 2 U — 1.1 72411_Kidney_HRE 27.0 B_Mesenchymal StemCells 94723_Donor 2 U — 4.2 73139_Uterus_Uterine smooth 2.9C_Mesenchymal Stem muscle cells Cells

[0974] TABLE OH Panel CNS_1 Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2031, Run Ag2839, Run Ag2031, Run Ag2839, Run TissueName 171620593 171669729 Tissue Name 171620593 171669729 BA4 Control18.8 27.9 BA17 PSP 12.0 14.6 BA4 Control2 27.9 43.8 BA17 PSP2 4.3 5.1BA4 3.3 3.1 Sub Nigra 55.1 67.8 Alzheimer's2 Control BA4 36.1 40.1 SubNigra 39.5 47.6 Parkinson's Control2 BA4 51.4 37.1 Sub Nigra 15.2 24.1Parkinson's2 Alzheimer's2 BA4 24.1 24.5 Sub Nigra 57.8 79.0 Huntington'sParkinson's2 BA4 3.3 2.5 Sub Nigra 86.5 100.0 Huntington's2 Huntington'sBA4 PSP 5.0 5.4 Sub Nigra 36.6 38.7 Huntington's2 BA4 PSP2 17.1 21.0 SubNigra 11.5 12.7 PSP2 BA4 8.9 10.0 Sub Nigra 5.9 9.3 DepressionDepression BA4 6.3 8.7 Sub Nigra 6.6 5.5 Depression2 Depression2 BA7Control 26.6 28.7 Glob Palladus 20.7 15.2 Control BA7 Control2 25.5 31.9Glob Palladus 10.2 7.7 Control2 BA7 4.8 4.7 Glob Palladus 13.5 20.0Alzheimer's2 Alzheimer's BA7 13.7 17.6 Glob Palladus 4.7 5.5 Parkinson'sAlzheimer's2 BA7 20.7 20.6 Glob Palladus 100.0 82.9 Parkinson's2Parkinson's BA7 24.0 34.2 Glob Palladus 12.6 18.6 Huntington'sParkinson's2 BA7 31.2 31.9 Glob Palladus 1.7 3.8 Huntington's2 PSP BA7PSP 15.2 20.9 Glob Palladus 4.1 4.9 PSP2 BA7 PSP2 13.0 18.4 GlobPalladus 4.2 4.3 Depression BA7 6.7 6.4 Temp Pole 8.4 9.6 DepressionControl BA9 Control 17.6 15.1 Temp Pole 32.1 43.8 Control2 BA9 Control251.4 75.8 Temp Pole 2.1 4.2 Alzheimer's BA9 2.2 2.8 Temp Pole 2.7 4.6Alzheimer's Alzheimer's2 BA9 6.8 7.1 Temp Pole 20.9 22.5 Alzheimer's2Parkinson's BA9 17.8 20.4 Temp Pole 18.4 23.3 Parkinson's Parkinson's2BA9 40.3 31.9 Temp Pole 32.3 37.6 Parkinson's2 Huntington's BA9 29.338.4 Temp Pole PSP 3.5 2.1 Huntington's BA9 8.3 8.0 Temp Pole 1.9 2.8Huntington's2 PSP2 BA9 PSP 8.7 8.2 Temp Pole 4.2 5.4 Depression2 BA9PSP2 3.4 1.9 Cing Gyr 42.3 64.6 Control BA9 4.7 4.4 Cing Gyr 26.8 27.0Depression Control2 BA9 3.8 4.8 Cing Gyr 13.0 20.0 Depression2Alzheimer's BA17 Control 27.7 32.1 Cing Gyr 3.3 5.2 Alzheimer's2 BA1728.1 33.2 Cing Gyr 34.6 37.9 Control2 Parkinson's BA17 2.8 3.1 Cing Gyr30.6 34.6 Alzheimer's2 Parkinson's2 BA17 27.2 30.1 Cing Gyr 50.7 66.0Parkinson's Huntington's BA17 25.2 22.1 Cing Gyr 26.2 33.0 Parkinson's2Huntington's2 BA17 15.3 18.8 Cing Gyr PSP 12.2 17.4 Huntington's BA177.4 10.5 Cing Gyr PSP2 5.4 6.8 Huntington's2 BA17 9.2 7.7 Cing Gyr 5.48.6 Depression Depression BA17 15.4 15.1 Cing Gyr 11.0 10.2 Depression2Depression2

[0975] CNS_neurodegeneration_v1.0 Summary: Ag2839 While no associationbetween the CG55910-01 gene and Alzheimer's disease is evident from theresults of this panel, this experiment confirms expression of this genein the brain. See Panel 1.3D for discussion of utility of this gene inthe central nervous system.

[0976] Panel 1.3D Summary: Ag2031/2839 Brain-specific expression of theCG55910-01 gene suggests a role for this gene in CNS processes.Polyunsaturated fatty acids (PUFAs), specifically the n-3 and n-6series, play a key role in the progression or prevention of humandiseases such as obesity, diabetes, cancer, and neurological and heartdisease. They function mainly by affecting cellular membrane lipidcomposition, metabolism, signal-transduction pathways, and by directcontrol of gene expression. Therefore, modulators of this gene productmay have utility in treating neurological diseases, such as Alzheimer'sdisease.

[0977] This gene is also moderately expressed in a variety of metabolictissues including pancreas, adrenal, thyroid, pituitary, adult and fetalheart, and adipose. This gene product appears to be differentiallyexpressed in fetal (CT value=30-32) vs adult skeletal muscle (CTvalue=34) and may be useful for the identification of the adult vs fetalsource of this tissue. This gene encodes a fatty acid desaturasehomolog. Fatty acid desaturases are on the metabolic pathway totriglyceride deposition. Thus, small molecule inhibition of this geneproduct may prevent the formation of fat and be effective in thetreatment for obesity.

[0978] Panel 2D Summary: Ag2839 The expression of the CG55910-01 geneappears to be highest in a sample derived from an ovarian cancer(CT=27.8). Of note is the difference in expression between this ovariancancer and its normal adjacent tissue. There is also expression in anumber of ovarian cancer samples in this panel. Thus, the expression ofthis gene could be used to distinguish this ovarian cancer from itsnormal adjacent tissue. Moreover, therapeutic modulation of this gene,through the use of small molecule drugs, antibodies or proteintherapeutics might be of benefit in the treatment of ovarian cancer.

[0979] Panel 4D Summary: Ag2031/2839 The CG55910-01 transcript is highlyexpressed in TNFalpha and Il-1 beta stimulated small airway epithelium,normal thymus, dermal fibroblasts, and NCI-H292 cells but not inleukocytes. This expression pattern is consistent with both sets ofprimers and probes. The expression profile suggests that the proteinencoded by this transcript could potentially regulate T cell developmentin the thymus and the response of small airway epithelium toproinflammatory cytokines. Thus, therapeutics designed with the proteinencoded by this transcript could be important in immune modulation andin the treatment of lung diseases such as asthma and COPD.

[0980] Panel 5D Summary: Ag2839 Expression of the CG55910-01 gene ismainly restricted to adipose. This gene encodes an acetyl coAdesaturase. Fatty acid desaturases are on the metabolic pathway totriglyceride deposition. Thus, small molecule inhibition of this geneproduct may prevent the formation of fat and be effective in thetreatment for obesity. Thus, therapeutic modulation of the expression orfunction of this gene may be effective in the treatment of obesity.

[0981] Panel CNS_(—)1 Summary: Ag2839 While no association between theCG55910-01 gene and any disease is evident from the results of thispanel, this experiment confirms expression of this gene in the brain.See Panel 1.3D for discussion of utility of this gene in the centralnervous system.

[0982] P. CG50281-01: 34 Wnt 10B like (NOV11)

[0983] Expression of gene CG50281-01 was assessed using the primer-probeset Ag2538, described in Table PA. Results of the RTQ-PCR runs are shownin Tables PB, PC, PD, PE and PF. TABLE PA Probe Name Ag2538 PrimersSequences Start Position SEQ ID NO Forward 5′-acaacgccttgactcttcttct-3′115 332 Probe TET-5′-aagacctccaagcctcagggactctg-3′-TAMRA 139 333 Reverse5′-acaagaagaaacaccccttgat-3′ 168 334

[0984] TABLE PB CNS_neurodegeneration_v1.0 Rel. Exp. (%) Ag2538, Rel.Exp. (%) Ag2538, Tissue Name Run 208779569 Tissue Name Run 208779569 AD1 Hippo 19.6 Control (Path) 3 5.2 Temporal Ctx AD 2 Hippo 35.4 Control(Path) 4 24.7 Temporal Ctx AD 3 Hippo 1.6 AD 1 Occipital Ctx 6.8 AD 4Hippo 0.0 AD 2 Occipital Ctx 0.0 (Missing) AD 5 Hippo 4.0 AD 3 OccipitalCtx 7.6 AD 6 Hippo 19.1 AD 4 Occipital Ctx 29.5 Control 2 Hippo 54.3 AD5 Occipital Ctx 12.6 Control 4 Hippo 5.2 AD 6 Occipital Ctx 7.6 Control(Path) 3 0.0 Control 1 Occipital 0.0 Hippo Ctx AD 1 Temporal Ctx 19.5Control 2 Occipital 49.3 Ctx AD 2 Temporal Ctx 38.2 Control 3 Occipital7.6 Ctx AD 3 Temporal Ctx 6.7 Control 4 Occipital 0.0 Ctx AD 4 TemporalCtx 4.2 Control (Path) 1 61.1 Occipital Ctx AD 5 Inf Temporal 43.5Control (Path) 2 2.6 Ctx Occipital Ctx AD 5 Sup Temporal 58.2 Control(Path) 3 2.8 Ctx Occipital Ctx AD 6 Inf Temporal 58.2 Control (Path) 428.3 Ctx Occipital Ctx AD 6 Sup Temporal 68.8 Control 1 Parietal 4.4 CtxCtx Control 1 Temporal 5.8 Control 2 Parietal 59.9 Ctx Ctx Control 2Temporal 41.2 Control 3 Parietal 9.0 Ctx Ctx Control 3 Temporal 18.3Control (Path) 1 100.0 Ctx Parietal Ctx Control 3 Temporal 21.5 Control(Path) 2 40.1 Ctx Parietal Ctx Control (Path) 1 83.5 Control (Path) 30.0 Temporal Ctx Parietal Ctx Control (Path) 2 58.6 Control (Path) 414.4 Temporal Ctx Parietal Ctx

[0985] TABLE PC Panel 1.3D Rel. Exp. (%) Rel. Exp. (%) Rel. Exp. (%)Rel. Exp. (%) Ag2538, Run Ag2538, Run Ag2538, Run Ag2538, Run TissueName 162187100 165639905 Tissue Name 162187100 165639905 Liver 0.0 0.0Kidney (fetal) 0.0 0.0 adenocarcinoma Pancreas 0.0 0.0 Renal ca. 786-00.0 0.0 Pancreatic ca. 0.0 0.0 Renal ca. 0.0 0.0 CAPAN 2 A498 Adrenalgland 0.0 0.0 Renal ca. RXF 10.2 42.3 393 Thyroid 0.0 0.0 Renal ca. 0.00.0 ACHN Salivary gland 0.0 0.0 Renal ca. UO- 0.0 0.0 31 Pituitary gland0.0 0.0 Renal ca. TK- 0.0 3.1 10 Brain (fetal) 18.0 46.7 Liver 0.0 0.0Brain (whole) 11.3 0.0 Liver (fetal) 0.0 0.0 Brain (amygdala) 22.2 59.9Liver ca. 0.0 0.0 (hepatoblast) HepG2 Brain (cerebellum) 0.0 0.0 Lung0.0 0.0 Brain 31.6 66.9 Lung (fetal) 0.0 0.0 (hippocampus) Brain(substantia 0.0 0.0 Lung ca. 0.0 0.0 nigra) (small cell) LX-1 Brain(thalamus) 0.0 10.5 Lung ca. 0.0 0.0 (small cell) NCI-H69 CerebralCortex 100.0 5.7 Lung ca. 0.0 0.0 (s.cell var.) SHP-77 Spinal cord 0.00.0 Lung ca. (large 0.0 58.6 cell)NCI-H460 glio/astro U87-MG 0.0 0.0Lung ca. (non- 0.0 0.0 sm. cell) A549 glio/astro U-118- 0.0 0.0 Lung ca.(non- 8.7 0.0 MG s.cell) NCI- H23 astrocytoma 0.0 0.0 Lung ca. (non- 0.00.0 SW1783 s.cell) HOP-62 neuro*; met SK-N- 7.7 0.0 Lung ca. (non- 0.00.0 AS s.cl) NCI- H522 astrocytoma SF- 0.0 0.0 Lung ca. 0.0 0.0 539(squam.) SW 900 astrocytoma SNB- 0.0 0.0 Lung ca. 0.0 0.0 75 (squam.)NCI- H596 glioma SNB-19 6.8 0.0 Mammary 0.0 0.0 gland glioma U251 0.00.0 Breast ca.* 7.2 0.0 (pl.ef) MCF-7 glioma SF-295 0.0 0.0 Breast ca.*0.0 0.0 (pl.ef) MDA- MB-231 Heart (fetal) 0.0 0.0 Breast ca.* 7.5 0.0(pl.ef) T47D Heart 0.0 0.0 Breast ca. BT- 0.0 15.6 549 Skeletal muscle4.5 0.0 Breast ca. 0.0 0.0 (fetal) MDA-N Skeletal muscle 0.0 0.0 Ovary0.0 0.0 Bone marrow 0.0 0.0 Ovarian ca. 0.0 0.0 OVCAR-3 Thymus 0.0 0.0Ovarian ca. 0.0 0.0 OVCAR-4 Spleen 0.0 0.0 Ovarian ca. 0.0 0.0 OVCAR-5Lymph node 0.0 11.1 Ovarian ca. 0.0 0.0 OVCAR-8 Colorectal 0.0 10.4Ovarian ca. 0.0 0.0 IGROV-1 Stomach 0.0 0.0 Ovarian ca.* 0.0 0.0(ascites) SK- OV-3 Small intestine 8.9 100.0 Uterus 0.0 0.0 Colon ca.SW480 0.0 0.0 Placenta 0.0 0.0 Colon ca.* 0.0 0.0 Prostate 0.0 0.0 SW620(SW480 met) Colon ca. HT29 0.0 0.0 Prostate ca.* 0.0 0.0 (bone met) PC-3Colon ca. HCT- 18.4 0.0 Testis 38.4 0.0 116 Colon ca. CaCo-2 10.6 0.0Melanoma 0.0 0.0 Hs688(A).T Colon ca. 0.0 0.0 Melanoma* 0.0 0.0 tissue(ODO3866) (met) Hs668(B).T Colon ca. HCC- 14.5 0.0 Melanoma 9.2 0.0 2998UACC-62 Gastric ca.* (liver 0.0 0.0 Melanoma 8.4 0.0 met) NCI-N87 M14Bladder 23.3 15.0 Melanoma 5.3 0.0 LOX IMVI Trachea 0.0 0.0 Melanoma*0.0 51.4 (met) SK- MEL-5 Kidney 0.0 0.0 Adipose 0.0 0.0

[0986] TABLE PD Panel 2D Rel. Exp. (%) Rel. Exp. (%) Ag2538, Ag2538,Tissue Name Run 161920580 Tissue Name Run 161920580 Normal Colon 9.7Kidney Margin 2.9 8120608 CC Well to Mod Diff 0.0 Kidney Cancer 0.0(ODO3866) 8120613 CC Margin (ODO3866) 9.8 Kidney Margin 0.0 8120614 CCGr.2 rectosigmoid 6.0 Kidney Cancer 0.0 (ODO3868) 9010320 CC Margin(ODO3868) 0.0 Kidney Margin 0.0 9010321 CC Mod Diff (ODO3920) 0.0 NormalUterus 0.0 CC Margin (ODO3920) 0.0 Uterus Cancer 064011 0.0 CC Gr.2ascend colon 0.0 Normal Thyroid 0.0 (ODO3921) CC Margin (ODO3921) 21.8Thyroid Cancer 0.0 064010 CC from Partial 0.0 Thyroid Cancer 8.4Hepatectomy (ODO4309) A302152 Mets Liver Margin (ODO4309) 0.0 ThyroidMargin 0.0 A302153 Colon mets to lung 0.0 Normal Breast 0.0 (OD04451-01)Lung Margin (OD04451- 0.0 Breast Cancer 0.0 02) (OD04566) NormalProstate 6546-1 0.0 Breast Cancer 8.0 (OD04590-01) Prostate Cancer 10.1Breast Cancer Mets 0.0 (OD04410) (OD04590-03) Prostate Margin 0.0 BreastCancer 0.0 (OD04410) Metastasis (OD04655-05) Prostate Cancer 0.0 BreastCancer 064006 0.0 (OD04720-01) Prostate Margin 0.0 Breast Cancer 10240.0 (OD04720-02) Normal Lung 061010 10.4 Breast Cancer 0.0 9100266 LungMet to Muscle 0.0 Breast Margin 0.0 (ODO4286) 9100265 Muscle Margin 0.0Breast Cancer 0.0 (ODO4286) A209073 Lung Malignant Cancer 0.0 BreastMargin 8.5 (OD03126) A2090734 Lung Margin (OD03126) 0.0 Normal Liver 0.0Lung Cancer (OD04404) 0.0 Liver Cancer 064003 0.0 Lung Margin (OD04404)0.0 Liver Cancer 1025 0.0 Lung Cancer (OD04565) 0.0 Liver Cancer 10260.0 Lung Margin (OD04565) 0.0 Liver Cancer 6004-T 0.0 Lung Cancer(OD04237- 0.0 Liver Tissue 6004-N 13.5 01) Lung Margin (OD04237- 0.0Liver Cancer 6005-T 0.0 02) Ocular Mel Met to Liver 0.0 Liver Tissue6005-N 0.0 (ODO4310) Liver Margin (ODO4310) 0.0 Normal Bladder 0.0Melanoma Mets to Lung 0.0 Bladder Cancer 1023 0.0 (OD04321) Lung Margin(OD04321) 0.0 Bladder Cancer 100.0 A302173 Normal Kidney 7.3 BladderCancer 46.3 (OD04718-01) Kidney Ca, Nuclear grade 0.0 Bladder Normal 0.02 (OD04338) Adjacent (OD04718- 03) Kidney Margin 8.4 Normal Ovary 0.0(OD04338) Kidney Ca Nuclear grade 8.3 Ovarian Cancer 0.0 1/2 (OD04339)064008 Kidney Margin 0.0 Ovarian Cancer 6.2 (OD04339) (OD04768-07)Kidney Ca, Clear cell 0.0 Ovary Margin 0.0 type (OD04340) (OD04768-08)Kidney Margin 0.0 Normal Stomach 0.0 (OD04340) Kidney Ca, Nuclear grade0.0 Gastric Cancer 0.0 3 (OD04348) 9060358 Kidney Margin 0.0 StomachMargin 0.0 (OD04348) 9060359 Kidney Cancer 0.0 Gastric Cancer 0.0(OD04622-01) 9060395 Kidney Margin 0.0 Stomach Margin 6.7 (OD04622-03)9060394 Kidney Cancer 0.0 Gastric Cancer 0.0 (OD04450-01) 9060397 KidneyMargin 0.0 Stomach Margin 0.0 (OD04450-03) 9060396 Kidney Cancer 81206070.0 Gastric Cancer 0.0 064005

[0987] TABLE PE Panel 3D Rel. Exp. (%) Rel. Exp. (%) Ag2538, Run Ag2538,Run Tissue Name 164843785 Tissue Name 164843785 Daoy-Medulloblastoma 0.0Ca Ski-Cervical epidermoid 0.0 carcinoma (metastasis)TE671-Medulloblastoma 0.0 ES-2-Ovarian clear cell 0.0 carcinoma D283Med- 6.1 Ramos-Stimulated with 0.0 Medulloblastoma PMA/ionomycin 6 hPFSK-1-Primitive 18.8 Ramos-Stimulated with 0.0 NeuroectodermalPMA/ionomycin 14 h XF-498-CNS 0.0 MEG-01-Chronic 0.0 myelogenousleukemia (megokaryoblast) SNB-78-Glioma 0.0 Raji-Burkitt's lymphoma 0.0SF-268-Glioblastoma 7.2 Daudi-Burkitt's lymphoma 0.0 T98G-Glioblastoma0.0 U266-B-cell plasmacytoma 8.2 SK-N-SH- 0.0 CA46-Burkitt's lymphoma0.0 Neuroblastoma (metastasis) SF-295-Glioblastoma 0.0 RL-non-Hodgkin'sB-cell 0.0 lymphoma Cerebellum 0.0 JM1-pre-B-cell lymphoma 0.0Cerebellum 0.0 Jurkat-T cell leukemia 0.0 NCI-H292- 0.0TF-1-Erythroleukemia 0.0 Mucoepidermoid lung carcinoma DMS-114-Smallcell 3.7 HUT 78-T-Cell lymphoma 0.0 lung cancer DMS-79-Small cell lung0.0 U937-Histiocytic lymphoma 0.0 cancer NCI-H146-Small cell 0.0KU-812-Myelogenous 0.0 lung cancer leukemia NCI-H526-Small cell 0.0769-P-Clear cell renal 0.0 lung cancer carcinoma NCI-N417-Small cell100.0 Caki-2-Clear cell renal 0.0 lung cancer carcinoma NCI-H82-Smallcell 2.3 SW 839-Clear cell renal 0.0 lung cancer carcinomaNCI-H157-Squamous 0.0 G401-Wilms' tumor 0.0 cell lung cancer(metastasis) NCI-H1155-Large cell 0.0 Hs766T-Pancreatic 0.0 lung cancercarcinoma (LN metastasis) NCI-H1299-Large cell 0.0 CAPAN-1-Pancreatic0.0 lung cancer adenocarcinoma (liver metastasis) NCI-H727-Lung 0.0SU86.86-Pancreatic 0.0 carcinoid carcinoma (liver metastasis)NCI-UMC-11-Lung 0.0 BxPC-3-Pancreatic 0.0 carcinoid adenocarcinomaLX-1-Small cell lung 0.0 HPAC-Pancreatic 0.0 cancer adenocarcinomaColo-205-Colon cancer 0.0 MIA PaCa-2-Pancreatic 0.0 carcinoma KM12-Coloncancer 0.0 CFPAC-1-Pancreatic ductal 0.0 adenocarcinoma KM20L2-Coloncancer 0.0 PANC-1-Pancreatic 0.0 epithelioid ductal carcinomaNCI-H716-Colon cancer 0.0 T24-Bladder carcinma 0.0 (transitional cell)SW-48-Colon 0.0 5637-Bladder carcinoma 0.0 adenocarcinoma SW1116-Colon7.2 HT-1197-Bladder carcinoma 0.0 adenocarcinoma LS 174T-Colon 0.0UM-UC-3-Bladder carcinma 0.0 adenocarcinoma (transitional cell)SW-948-Colon 0.0 A204-Rhabdomyosarcoma 0.0 adenocarcinoma SW-480-Colon0.0 HT-1080-Fibrosarcoma 0.0 adenocarcinoma NCI-SNU-5-Gastric 0.0MG-63-Osteosarcoma 0.0 carcinoma KATO III-Gastric 0.0SK-LMS-1-Leiomyosarcoma 0.0 carcinoma (vulva) NCI-SNU-16-Gastric 0.0SJRH30-Rhabdomyosarcoma 0.0 carcinoma (met to bone marrow)NCI-SNU-1-Gastric 0.0 A431-Epidermoid carcinoma 0.0 carcinomaRF-1-Gastric 0.0 WM266-4-Melanoma 5.0 adenocarcinoma RF-48-Gastric 0.0DU 145-Prostate carcinoma 0.0 adenocarcinoma (brain metastasis)MKN-45-Gastric 0.0 MDA-MB-468-Breast 0.0 carcinoma adenocarcinomaNCI-N87-Gastric 0.0 SCC-4-Squamous cell 0.0 carcinoma carcinoma oftongue OVCAR-5-Ovarian 0.0 SCC-9-Squamous cell 0.0 carcinoma carcinomaof tongue RL95-2-Uterine 0.0 SCC-15-Squamous cell 0.0 carcinomacarcinoma of tongue HelaS3-Cervical 0.0 CAL 27-Squamous cell 12.3adenocarcinoma carcinoma of tongue

[0988] TABLE PF Panel 4D Rel. Exp. (%) Rel. Exp. (%) Ag2538, Run Ag2538,Run Tissue Name 164034950 Tissue Name 164034950 Secondary Th1 act 0.0HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 SecondaryTr1 act 6.0 HUVEC TNF alpha + IFN 0.0 gamma Secondary Th1 rest 0.0 HUVECTNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1rest 0.0 Lung Microvascular EC 0.0 none Primary Th1 act 0.0 LungMicrovascular EC 0.0 TNFalpha + IL-1beta Primary Th2 act 6.2Microvascular Dermal EC 0.0 none Primary Tr1 act 6.7 MicrosvasularDermal EC 0.0 TNFalpha + IL-1beta Primary Th1 rest 0.0 Bronchialepithelium 0.0 TNFalpha + IL1beta Primary Th2 rest 0.0 Small airwayepithelium 0.0 none Primary Tr1 rest 4.2 Small airway epithelium 0.0TNFalpha + IL-1beta CD45RA CD4 0.0 Coronery artery SMC rest 0.0lymphocyte act CD45RO CD4 0.0 Coronery artery SMC 0.0 lymphocyte actTNFalpha + IL-1beta CD8 lymphocyte act 0.0 Astrocytes rest 0.0 SecondaryCD8 0.0 Astrocytes TNFalpha + 0.0 lymphocyte rest IL-1beta Secondary CD86.9 KU-812 (Basophil) rest 0.0 lymphocyte act CD4 lymphocyte none 6.6KU-812 (Basophil) 0.0 PMA/ionomycin 2ry Th1/Th2/Tr1_anti- 0.0 CCD1106(Keratinocytes) 0.0 CD95 CH11 none LAK cells rest 3.5 CCD1106(Keratinocytes) 0.0 TNFalpha + IL-1beta LAK cells IL-2 7.6 Livercirrhosis 19.2 LAK cells IL-2+IL-12 0.0 Lupus kidney 0.0 LAK cellsIL-2+IFN 0.0 NCI-H292 none 0.0 gamma LAK cells IL-2+ IL-18 0.0 NCI-H292IL-4 0.0 LAK cells 8.4 NCI-H292 IL-9 9.6 PMA/ionomycin NK Cells IL-2rest 3.1 NCI-H292 IL-13 7.1 Two Way MLR 3 day 8.5 NCI-H292 IFN gamma 0.0Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNFalpha + IL-1 0.0 beta PBMC rest 0.0 Lung fibroblast none 0.0 PBMC PWM0.0 Lung fibroblast TNF alpha 0.0 + IL-1 beta PBMC PHA-L 0.0 Lungfibroblast IL-4 0.0 Ramos (B cell) none 4.2 Lung fibroblast IL-9 0.0Ramos (B cell) 11.7 Lung fibroblast IL-13 0.0 ionomycin B lymphocytesPWM 3.8 Lung fibroblast IFN 0.0 gamma B lymphocytes CD40L 0.0 Dermalfibroblast 0.0 and IL-4 CCD1070 rest EOL-1 dbcAMP 11.5 Dermal fibroblast10.6 CCD1070 TNF alpha EOL-1 dbcAMP 60.3 Dermal fibroblast 0.0PMA/ionomycin CCD1070 IL-1 beta Dendritic cells none 0.0 Dermalfibroblast IFN 0.0 gamma Dendritic cells LPS 0.0 Dermal fibroblast IL-40.0 Dendritic cells anti- 0.0 IBD Colitis 2 7.9 CD40 Monocytes rest 0.0IBD Crohn's 7.1 Monocytes LPS 0.0 Colon 100.0 Macrophages rest 1.4 Lung27.7 Macrophages LPS 4.7 Thymus 0.0 HUVEC none 0.0 Kidney 0.0 HUVECstarved 0.0

[0989] CNS_neurodegeneration_v1.0 Summary: Ag2538 While no associationbetween expression of the CG50281-01 gene and Alzheimer's disease isapparent in this panel, the profile here confirms expression of thisgene in the brain. See Panel 1.3D for discussion of potential utility ofthis gene in the brain.

[0990] Panel 1.3D Summary: Ag2538 This gene encodes a Wnt 10b homolog,with low but significant expression in the brain in two experiments withthe same probe and primer set. Wnt 10b is downstream of sonic hedgehogin follicular development. Sonic hedgehog regulates hair growth and whenexpressed in follicles can induce new hair growth. Therefore, expressionof this gene by gene therapy may have therapeutic utility in thetreatment of hair loss.

[0991] The wnt pathway has also been implicated in Alzheimer's disease.Agents that potentiate the signaling of this gene product may thus haveutility in the treatment of neurodegenerative diseases such asAlzheimer's disease.

[0992] In addition, expression of this gene is extremely low in thecancer cell lines on this panel, suggesting that a decrease inexpression correlates to cell proliferation.

[0993] Panel 2D Summary: Ag2538 The expression of the CG50281-01 gene issignificantly increased in bladder cancer compared to normal bladdersamples. These data indicate that the expression of this gene might beassociated with bladder cancer and may be used as a diagnostic marker ofdisease. Thus, therapeutic modulation of the gene product by antibodies,small molecule inhibitors and chimeric molecules might be of use in thetreatment of bladder cancer.

[0994] Panel 3D Summary: Ag2538 Expression of the CG50281-01 gene islimited to few cell lines on this panel including a lung cancer cellline and a cell line derived from squamous carcinoma of the tongue.Thus, expression of this gene could be used to differentiate thesesamples from other samples on this panel.

Example 3 SNP Analysis of NOVX Clones

[0995] SeqCalling™ Technology: cDNA was derived from various humansamples representing multiple tissue types, normal and diseased states,physiological states, and developmental states from different donors.Samples were obtained as whole tissue, cell lines, primary cells ortissue cultured primary cells and cell lines. Cells and cell lines mayhave been treated with biological or chemical agents that regulate geneexpression for example, growth factors, chemokines, steroids. The cDNAthus derived was then sequenced using CuraGen's proprietary SeqCallingtechnology. Sequence traces were evaluated manually and edited forcorrections if appropriate. cDNA sequences from all samples wereassembled with themselves and with public ESTs using bioinformaticsprograms to generate CuraGen's human SeqCalling database of SeqCallingassemblies. Each assembly contains one or more overlapping cDNAsequences derived from one or more human samples. Fragments and ESTswere included as components for an assembly when the extent of identitywith another component of the assembly was at least 95% over 50 bp. Eachassembly can represent a gene and/or its variants such as splice formsand/or single nucleotide polymorphisms (SNPs) and their combinations.

[0996] Variant sequences are included in this application. A variantsequence can include a single nucleotide polymorphism (SNP). A SNP can,in some instances, be referred to as a “cSNP” to denote that thenucleotide sequence containing the SNP originates as a cDNA. A SNP canarise in several ways. For example, a SNP may be due to a substitutionof one nucleotide for another at the polymorphic site. Such asubstitution can be either a transition or a transversion. A SNP canalso arise from a deletion of a nucleotide or an insertion of anucleotide, relative to a reference allele. In this case, thepolymorphic site is a site at which one allele bears a gap with respectto a particular nucleotide in another allele. SNPs occurring withingenes may result in an alteration of the amino acid encoded by the geneat the position of the SNP. Intragenic SNPs may also be silent, however,in the case that a codon including a SNP encodes the same amino acid asa result of the redundancy of the genetic code. SNPs occurring outsidethe region of a gene, or in an intron within a gene, do not result inchanges in any amino acid sequence of a protein but may result inaltered regulation of the expression pattern for example, alteration intemporal expression, physiological response regulation, cell typeexpression regulation, intensity of expression, stability of transcribedmessage.

[0997] Method of novel SNP Identification: SNPs are identified byanalyzing sequence assemblies using CuraGen's proprietary SNPToolalgorithm. SNPTool identifies variation in assemblies with the followingcriteria: SNPs are not analyzed within 10 base pairs on both ends of analignment; Window size (number of bases in a view) is 10; The allowednumber of mismatches in a window is 2; Minimum SNP base quality (PHREDscore) is 23; Minimum number of changes to score an SNP is 2/assemblyposition. SNPTool analyzes the assembly and displays SNP positions,associated individual variant sequences in the assembly, the depth ofthe assembly at that given position, the putative assembly allelefrequency, and the SNP sequence variation. Sequence traces are thenselected and brought into view for manual validation. The consensusassembly sequence is imported into CuraTools along with variant sequencechanges to identify potential amino acid changes resulting from the SNPsequence variation. Comprehensive SNP data analysis is then exportedinto the SNPCalling database.

[0998] Method of novel SNP Confirmation: SNPs are confirmed employing avalidated method know as Pyrosequencing (Pyrosequencing, Westborough,Mass.). Detailed protocols for Pyrosequencing can be found in: Alderbomet al. Determination of Single Nucleotide Polymorphisms by Real-timePyrophosphate DNA Sequencing. (2000). Genome Research. 10, Issue 8,August. 1249-1265. In brief, Pyrosequencing is a real time primerextension process of genotyping. This protocol takes double-stranded,biotinylated PCR products from genomic DNA samples and binds them tostreptavidin beads. These beads are then denatured producing singlestranded bound DNA. SNPs are characterized utilizing a technique basedon an indirect bioluminometric assay of pyrophosphate (PPi) that isreleased from each dNTP upon DNA chain elongation. Following Klenowpolymerase-mediated base incorporation, PPi is released and used as asubstrate, together with adenosine 5′-phosphosulfate (APS), for ATPsulfurylase, which results in the formation of ATP. Subsequently, theAT? accomplishes the conversion of luciferin to its oxi-derivative bythe action of luciferase. The ensuing light output becomes proportionalto the number of added bases, up to about four bases. To allowprocessivity of the method dNTP excess is degraded by apyrase, which isalso present in the starting reaction mixture, so that only dNTPs areadded to the template during the sequencing. The process has been fullyautomated and adapted to a 96-well format, which allows rapid screeningof large SNP panels. The DNA and protein sequences for the novel singlenucleotide polymorphic variants are reported. Variants are reportedindividually but any combination of all or a select subset of variantsare also included. In addition, the positions of the variant bases andthe variant amino acid residues are underlined.

[0999] Results

[1000] Variants are reported individually but any combination of all ora select subset of variants are also included as contemplated NOVXembodiments of the invention.

[1001] NOV1 TABLE 21 cSNP and Coding Variants for NOV1 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13375592 221 A G Arg-> Gly at aa 72 13373919 299 G C Ala -> Pro at aa 98 13373884 301 T Csilent 13373885 399 C T Ser -> Leu at aa 131 13375593 428 G A Gly -> Serat aa 141 13375594 735 C A Thr -> Asn at aa 243 13375595 867 A G Asp ->Gly at aa 287

[1002] NOV4 TABLE 22 cSNP and Coding Variants for NOV4 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13375361  809 G AVal -> Ile at aa 258 13375360 1062 C T silent

[1003] NOV7 TABLE 23 cSNP and Coding Variants for NOV7 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13375931 289 A T Ser-> Cys at aa 87

[1004] NOV9 TABLE 24 cSNP and Coding Variants for NOV9 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13376492 298 C G Asn-> Lys at aa 53 13376491 551 C G His -> Asp at aa 138

[1005] NOV11 TABLE 25 cSNP and Coding Variants for NOV9 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13376495 864 G A Gly-> Asp at aa 204 13376494 1051 G A silent 13376493 1171 C T silent

[1006] NOV12a TABLE 26 cSNP and Coding Variants for NOV12a Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13376475 156 C Tsilent 13376474 407 T C Ile -> Thr at aa 105 13376473 413 A G Asn -> Serat aa 107 13376472 549 A G silent 13376471 841 G A Val -> Met at aa 250

[1007] NOV12b

[1008] One or more consensus positions (Cons. Pos.) of the nucleotidesequence have been identified as SNPs. “Depth” represents the number ofclones covering the region of the SNP. The Putative Allele Frequency(Putative Allele Freq.) is the fraction of all the clones containing theSNP. TABLE 27 cSNP and Coding Variants for NOV12b Cons. Pos. Depth WildType Variant Putative Allele Freq. 964 46 T C 0.065 973 46 T A 0.065

[1009] NOV13 TABLE 28 cSNP and Coding Variants for NOV13 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13376476 461 T Csilent

[1010] NOV15a TABLE 29 cSNP and Coding Variants for NOV15a Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13376483 229 T C Ser-> Pro at aa 27 13376484 265 A G Lys -> Glu at aa 39 13376485 315 G Asilent 13376486 376 A G Arg -> Gly at aa 76 13376487 465 C T silent13374260 808 G A Ala -> Thr at aa 220 13374259 857 A G Gln -> Arg at aa236 13374258 958 G A Gly -> Arg at aa 270

[1011] NOV15d

[1012] One or more consensus positions (Cons. Pos.) of the nucleotidesequence have been identified as SNPs as shown in Table 2. “Depth”represents the number of clones covering the region of the SNP. ThePutative Allele Frequency (Putative Allele Freq.) is the fraction of allthe clones containing the SNP. TABLE 30 cSNP and Coding Variants forNOV15d Cons. Pos. Depth Wild Type Variant Putative Allele Freq. 494 50 GA 0.040 512 49 G T 0.184 569 70 A G 0.043 679 113 G A 0.018 682 113 G A0.018 687 114 G A 0.026 731 114 A G 0.018 736 114 A G 0.035 751 113 C T0.018 759 114 T C 0.026 763 114 A G 0.018 792 132 A C 0.030 794 132 A T0.015 800 132 A G 0.015 840 169 G A 0.012 847 169 A G 0.024 856 171 T C0.064 861 171 C T 0.023 1151 55 T A 0.036 1152 55 T C 0.036 1228 80 G T0.025 1234 81 C T 0.025 1333 87 T C 0.023 1431 91 G A 0.022 1456 90 A G0.022 1493 89 A G 0.022 1530 71 G A 0.028 1727 120 A G 0.025 1756 78 T C0.026 1845 67 T C 0.030 1857 67 C T 0.239 1885 59 G A 0.034 7552 19 C T0.263

[1013] NOV16 TABLE 31 cSNP and Coding Variants for NOV16 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13375814 267 C Tsilent 13375816 488 A G Asn -> Ser at aa 153 13375815 690 C A silent

[1014] NOV19 TABLE 32 cSNP and Coding Variants for NOV19 Base PositionVariant of cSNP Wild Type Variant Amino Acid Change 13374210 237 G A Ser-> Asn at aa 36 13374212 3536 A G Thr -> Ala at aa 1136 13374213 3567 AG Gln -> Arg at aa 1146

[1015] One or more consensus positions (Cons. Pos.) of the nucleotidesequence have been identified as SNPs as shown in Table 2. “Depth”represents the number of clones covering the region of the SNP. ThePutative Allele Frequency (Putative Allele Freq.) is the fraction of allthe clones containing the SNP. TABLE 33 cSNP and Coding Variants forNOV20 Cons. Pos. Depth Wild Type Variant Putative Allele Freq. 212 8 G A0.250 311 12 A G 0.250 523 9 A G 0.222 554 8 A G 0.250

Other Embodiments

[1016] Although particular embodiments have been disclosed herein indetail, this has been done by way of example for purposes ofillustration only, and is not intended to be limiting with respect tothe scope of the appended claims, which follow. In particular, it iscontemplated by the inventors that various substitutions, alterations,and modifications may be made to the invention without departing fromthe spirit and scope of the invention as defined by the claims. Thechoice of nucleic acid starting material, clone of interest, or librarytype is believed to be a matter of routine for a person of ordinaryskill in the art with knowledge of the embodiments described herein.Other aspects, advantages, and modifications considered to be within thescope of the following claims.

0 SEQUENCE LISTING The patent application contains a lengthy “SequenceListing” section. A copy of the “Sequence Listing” is available inelectronic form from the USPTO web site(http://seqdata.uspto.gov/sequence.html?DocID=20040022781). Anelectronic copy of the “Sequence Listing” will also be available fromthe USPTO upon request and payment of the fee set forth in 37 CFR1.19(b)(3).

What is claimed is:
 1. An isolated polypeptide comprising an amino acidsequence selected from the group consisting of: (a) a mature form of anamino acid sequence selected from the group consisting of SEQ ID NOS: 2,4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40,42, 44, 46, 48, 50, 52, 54, 56, 58, and 60; (b) a variant of a matureform of an amino acid sequence selected from the group consisting of SEQID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60, wherein one ormore amino acid residues in said variant differs from the amino acidsequence of said mature form, provided that said variant differs in nomore than 15% of the amino acid residues from the amino acid sequence ofsaid mature form; (c) an amino acid sequence selected from the groupconsisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and60; and (d) a variant of an amino acid sequence selected from the groupconsisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and60 wherein one or more amino acid residues in said variant differs fromthe amino acid sequence of said mature form, provided that said variantdiffers in no more than 15% of amino acid residues from said amino acidsequence.
 2. The polypeptide of claim 1, wherein said polypeptidecomprises the amino acid sequence of a naturally-occurring allelicvariant of an amino acid sequence selected from the group consisting ofSEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and
 60. 3. Thepolypeptide of claim 2, wherein said allelic variant comprises an aminoacid sequence that is the translation of a nucleic acid sequencediffering by a single nucleotide from a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53,55, 57, and
 59. 4. The polypeptide of claim 1, wherein the amino acidsequence of said variant comprises a conservative amino acidsubstitution.
 5. An isolated nucleic acid molecule comprising a nucleicacid sequence encoding a polypeptide comprising an amino acid sequenceselected from the group consisting of: (a) a mature form of an aminoacid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6,8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42,44, 46, 48, 50, 52, 54, 56, 58, and 60; (b) a variant of a mature formof an amino acid sequence selected from the group consisting of SEQ IDNOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36,38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60, wherein one or moreamino acid residues in said variant differs from the amino acid sequenceof said mature form, provided that said variant differs in no more than15% of the amino acid residues from the amino acid sequence of saidmature form; (c) an amino acid sequence selected from the groupconsisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and60; (d) a variant of an amino acid sequence selected from the groupconsisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and60, wherein one or more amino acid residues in said variant differs fromthe amino acid sequence of said mature form, provided that said variantdiffers in no more than 15% of amino acid residues from said amino acidsequence; (e) a nucleic acid fragment encoding at least a portion of apolypeptide comprising an amino acid sequence chosen from the groupconsisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and60, or a variant of said polypeptide, wherein one or more amino acidresidues in said variant differs from the amino acid sequence of saidmature form, provided that said variant differs in no more than 15% ofamino acid residues from said amino acid sequence; and (f) a nucleicacid molecule comprising the complement of (a), (b), (c), (d) or (e). 6.The nucleic acid molecule of claim 5, wherein the nucleic acid moleculecomprises the nucleotide sequence of a naturally-occurring allelicnucleic acid variant.
 7. The nucleic acid molecule of claim 5, whereinthe nucleic acid molecule encodes a polypeptide comprising the aminoacid sequence of a naturally-occurring polypeptide variant.
 8. Thenucleic acid molecule of claim 5, wherein the nucleic acid moleculediffers by a single nucleotide from a nucleic acid sequence selectedfrom the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53,55, 57, and
 59. 9. The nucleic acid molecule of claim 5, wherein saidnucleic acid molecule comprises a nucleotide sequence selected from thegroup consisting of (a) a nucleotide sequence selected from the groupconsisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25,27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, and 59;(b) a nucleotide sequence differing by one or more nucleotides from anucleotide sequence selected from the group consisting of SEQ ID NOS: 1,3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39,41, 43, 45, 47, 49, 51, 53, 55, 57, and 59, provided that no more than20% of the nucleotides differ from said nucleotide sequence; (c) anucleic acid fragment of (a); and (d) a nucleic acid fragment of (b).10. The nucleic acid molecule of claim 5, wherein said nucleic acidmolecule hybridizes under stringent conditions to a nucleotide sequencechosen from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49,51, 53, 55, 57, and 59, or a complement of said nucleotide sequence. 11.The nucleic acid molecule of claim 5, wherein the nucleic acid moleculecomprises a nucleotide sequence selected from the group consisting of(a) a first nucleotide sequence comprising a coding sequence differingby one or more nucleotide sequences from a coding sequence encoding saidamino acid sequence, provided that no more than 20% of the nucleotidesin the coding sequence in said first nucleotide sequence differ fromsaid coding sequence; (b) an isolated second polynucleotide that is acomplement of the first polynucleotide; and (c) a nucleic acid fragmentof (a) or (b).
 12. A vector comprising the nucleic acid molecule ofclaim
 11. 13. The vector of claim 12, further comprising a promoteroperably-linked to said nucleic acid molecule.
 14. A cell comprising thevector of claim
 12. 15. An antibody that immunospecifically-binds to thepolypeptide of claim
 1. 16. The antibody of claim 15, wherein saidantibody is a monoclonal antibody.
 17. The antibody of claim 15, whereinthe antibody is a humanized antibody.
 18. A method for determining thepresence or amount of the polypeptide of claim 1 in a sample, the methodcomprising: (a) providing the sample; (b) contacting the sample with anantibody that binds immunospecifically to the polypeptide; and (c)determining the presence or amount of antibody bound to saidpolypeptide, thereby determining the presence or amount of polypeptidein said sample.
 19. A method for determining the presence or amount ofthe nucleic acid molecule of claim 5 in a sample, the method comprising:(a) providing the sample; (b) contacting the sample with a probe thatbinds to said nucleic acid molecule; and (c) determining the presence oramount of the probe bound to said nucleic acid molecule, therebydetermining the presence or amount of the nucleic acid molecule in saidsample.
 20. A method of identifying an agent that binds to a polypeptideof claim 1, the method comprising: (a) contacting said polypeptide withsaid agent; and (b) determining whether said agent binds to saidpolypeptide.
 21. A method for identifying an agent that modulates theexpression or activity of the polypeptide of claim 1, the methodcomprising: (a) providing a cell expressing said polypeptide; (b)contacting the cell with said agent; and (c) determining whether theagent modulates expression or activity of said polypeptide, whereby analteration in expression or activity of said peptide indicates saidagent modulates expression or activity of said polypeptide.
 22. A methodfor modulating the activity of the polypeptide of claim 1, the methodcomprising contacting a cell sample expressing the polypeptide of saidclaim with a compound that binds to said polypeptide in an amountsufficient to modulate the activity of the polypeptide.
 23. A method oftreating or preventing a NOVX-associated disorder, said methodcomprising administering to a subject in which such treatment orprevention is desired the polypeptide of claim 1 in an amount sufficientto treat or prevent said NOVX-associated disorder in said subject. 24.The method of claim 23, wherein said subject is a human.
 25. A method oftreating or preventing a NOVX-associated disorder, said methodcomprising administering to a subject in which such treatment orprevention is desired the nucleic acid of claim 5 in an amountsufficient to treat or prevent said NOVX-associated disorder in saidsubject.
 26. The method of claim 25, wherein said subject is a human.27. A method of treating or preventing a NOVX-associated disorder, saidmethod comprising administering to a subject in which such treatment orprevention is desired the antibody of claim 15 in an amount sufficientto treat or prevent said NOVX-associated disorder in said subject. 28.The method of claim 27, wherein the subject is a human.
 29. Apharmaceutical composition comprising the polypeptide of claim 1 and apharmaceutically-acceptable carrier.
 30. A pharmaceutical compositioncomprising the nucleic acid molecule of claim 5 and apharmaceutically-acceptable carrier.
 31. A pharmaceutical compositioncomprising the antibody of claim 15 and a pharmaceutically-acceptablecarrier.
 32. A kit comprising in one or more containers, thepharmaceutical composition of claim
 29. 33. A kit comprising in one ormore containers, the pharmaceutical composition of claim
 30. 34. A kitcomprising in one or more containers, the pharmaceutical composition ofclaim
 31. 35. The use of a therapeutic in the manufacture of amedicament for treating a syndrome associated with a human disease, thedisease selected from a NOVX-associated disorder, wherein saidtherapeutic is selected from the group consisting of a NOVX polypeptide,a NOVX nucleic acid, and a NOVX antibody.
 36. A method for screening fora modulator of activity or of latency or predisposition to aNOVX-associated disorder, said method comprising: (a) administering atest compound to a test animal at increased risk for a NOVX-associateddisorder, wherein said test animal recombinantly expresses thepolypeptide of claim 1; (b) measuring the activity of said polypeptidein said test animal after administering the compound of step (a); (c)comparing the activity of said protein in said test animal with theactivity of said polypeptide in a control animal not administered saidpolypeptide, wherein a change in the activity of said polypeptide insaid test animal relative to said control animal indicates the testcompound is a modulator of latency of or predisposition to aNOVX-associated disorder.
 37. The method of claim 36, wherein said testanimal is a recombinant test animal that expresses a test proteintransgene or expresses said transgene under the control of a promoter atan increased level relative to a wild-type test animal, and wherein saidpromoter is not the native gene promoter of said transgene.
 38. A methodfor determining the presence of or predisposition to a diseaseassociated with altered levels of the polypeptide of claim 1 in a firstmammalian subject, the method comprising: (a) measuring the level ofexpression of the polypeptide in a sample from the first mammaliansubject; and (b) comparing the amount of said polypeptide in the sampleof step (a) to the amount of the polypeptide present in a control samplefrom a second mammalian subject known not to have, or not to bepredisposed to, said disease, wherein an alteration in the expressionlevel of the polypeptide in the first subject as compared to the controlsample indicates the presence of or predisposition to said disease. 39.A method for determining the presence of or predisposition to a diseaseassociated with altered levels of the nucleic acid molecule of claim 5in a first mammalian subject, the method comprising: (a) measuring theamount of the nucleic acid in a sample from the first mammalian subject;and (b) comparing the amount of said nucleic acid in the sample of step(a) to the amount of the nucleic acid present in a control sample from asecond mammalian subject known not to have or not be predisposed to, thedisease; wherein an alteration in the level of the nucleic acid in thefirst subject as compared to the control sample indicates the presenceof or predisposition to the disease.
 40. A method of treating apathological state in a mammal, the method comprising administering tothe mammal a polypeptide in an amount that is sufficient to alleviatethe pathological state, wherein the polypeptide is a polypeptide havingan amino acid sequence at least 95% identical to a polypeptidecomprising an amino acid sequence of at least one of SEQ ID NOS: 2, 4,6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40,42, 44, 46, 48, 50, 52, 54, 56, 58, and 60, or a biologically activefragment thereof.
 41. A method of treating a pathological state in amammal, the method comprising administering to the mammal the antibodyof claim 15 in an amount sufficient to alleviate the pathological state.